AVAHO

Working night shifts has been associated with an increased risk for certain cancers, as well as other health disorders. Indeed, the World Health Organization’s International Agency for Research on Cancer (IARC) has classified night shift work as “probably carcinogenic to humans.”

But why night shift should elevate the risk for cancer has been unclear.

A new study shows that a simulated night shift schedule significantly altered the normal circadian rhythmicity of genes that are involved in cancer hallmark pathways. It also found that this circadian misalignment caused circadian dysregulation of genes involved in key DNA repair pathways.

“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s biological sciences division in Richland, Wash.

The study was published online in the Journal of Pineal Research.
 

Study conducted among volunteers 

The study was carried out among healthy volunteers who were subjected to simulated night shift or day shift schedules.

The cohort comprised 14 adults between the ages of 22 and 34 years who had normal nighttime sleep schedules. They were randomly assigned (seven in each group) to a simulated day shift schedule that involved 3 days of daytime wakefulness (6 a.m.-10 p.m.), or a simulated night shift schedule involving 3 days of nighttime wakefulness (6 p.m.-10 a.m.).

After the 3 days of simulated shift work, all participants were then kept in a constant routine protocol (used to study humans’ internally generated biological rhythms independent of any external influences). As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under laboratory conditions with constant light exposure and room temperature and evenly distributed food intake (hourly isocaloric snacks).

Blood samples were collected at 3-hour intervals and used for leukocyte transcriptome analysis and DNA damage assessment.

The authors found that the circadian expression of canonical clock genes was substantially altered by the simulated night shift schedule vs. the day shift schedule. Four genes (CRY1, CRY2, PER2, and NR1D2) lost their normal day-shift rhythmicity following the night shift schedule, and NPAS2 gene expression was not rhythmic during the day shift but exhibited circadian rhythmicity in the simulated night shift condition. Three other genes (NR1D1, PER3, and DBP) were significantly rhythmic during both shifts.

The team also looked at the effect of night shift on circadian rhythmicity in cancer hallmark genes, using a panel of 726 genes. The analysis showed that:

• 257 (35.4%) were rhythmic after at least one of the two simulated shift work conditions.
• 113 (15.6%) were rhythmic in day shift only.
• 96 (13.2%) were rhythmic during night shift only.
• 48 (6.6%) were rhythmic during both shifts.

A subset of 10 (1.4%) genes exhibited a significant phase advance (3.7 to 8.3 hours) or phase delay (2.8 to 7.0 hours) during the night shift vs. the day shift.

Thus, the authors concluded, shift work caused significant disturbances in the rhythmicity of gene expression in cancer hallmark pathways.

Findings also showed that night shift work increases endogenous and exogenous DNA damage. Endogenous DNA damage was generally higher after the night shift compared to the day shift, and across the 24-hour constant routine the percentage of cells with BRCA1 and g H2AX foci was significantly higher for night shift.
 

Next steps

The team said that the next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk for cancer.

If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes, they suggested.  

“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” co-senior author Hans Van Dongen, PhD, a professor at Washington State University in Pullman and director of the WSU Sleep and Performance Research Center, Spokane, said in a statement. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”

The study was supported by start-up funds from Washington State University and a Center for Human Health and the Environment grant from North Carolina State University, and in part by the United States Army Medical Research and Development Command, the National Institutes of Health, CDMRP (Congressionally Directed Medical Research Programs) Peer Reviewed Cancer Research Program award, and the BRAVE investment.

The authors have disclosed no relevant financial relationships.

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

Working night shifts has been associated with an increased risk for certain cancers, as well as other health disorders. Indeed, the World Health Organization’s International Agency for Research on Cancer (IARC) has classified night shift work as “probably carcinogenic to humans.”

But why night shift should elevate the risk for cancer has been unclear.

A new study shows that a simulated night shift schedule significantly altered the normal circadian rhythmicity of genes that are involved in cancer hallmark pathways. It also found that this circadian misalignment caused circadian dysregulation of genes involved in key DNA repair pathways.

“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s biological sciences division in Richland, Wash.

The study was published online in the Journal of Pineal Research.
 

Study conducted among volunteers 

The study was carried out among healthy volunteers who were subjected to simulated night shift or day shift schedules.

The cohort comprised 14 adults between the ages of 22 and 34 years who had normal nighttime sleep schedules. They were randomly assigned (seven in each group) to a simulated day shift schedule that involved 3 days of daytime wakefulness (6 a.m.-10 p.m.), or a simulated night shift schedule involving 3 days of nighttime wakefulness (6 p.m.-10 a.m.).

After the 3 days of simulated shift work, all participants were then kept in a constant routine protocol (used to study humans’ internally generated biological rhythms independent of any external influences). As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under laboratory conditions with constant light exposure and room temperature and evenly distributed food intake (hourly isocaloric snacks).

Blood samples were collected at 3-hour intervals and used for leukocyte transcriptome analysis and DNA damage assessment.

The authors found that the circadian expression of canonical clock genes was substantially altered by the simulated night shift schedule vs. the day shift schedule. Four genes (CRY1, CRY2, PER2, and NR1D2) lost their normal day-shift rhythmicity following the night shift schedule, and NPAS2 gene expression was not rhythmic during the day shift but exhibited circadian rhythmicity in the simulated night shift condition. Three other genes (NR1D1, PER3, and DBP) were significantly rhythmic during both shifts.

The team also looked at the effect of night shift on circadian rhythmicity in cancer hallmark genes, using a panel of 726 genes. The analysis showed that:

• 257 (35.4%) were rhythmic after at least one of the two simulated shift work conditions.
• 113 (15.6%) were rhythmic in day shift only.
• 96 (13.2%) were rhythmic during night shift only.
• 48 (6.6%) were rhythmic during both shifts.

A subset of 10 (1.4%) genes exhibited a significant phase advance (3.7 to 8.3 hours) or phase delay (2.8 to 7.0 hours) during the night shift vs. the day shift.

Thus, the authors concluded, shift work caused significant disturbances in the rhythmicity of gene expression in cancer hallmark pathways.

Findings also showed that night shift work increases endogenous and exogenous DNA damage. Endogenous DNA damage was generally higher after the night shift compared to the day shift, and across the 24-hour constant routine the percentage of cells with BRCA1 and g H2AX foci was significantly higher for night shift.
 

Next steps

The team said that the next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk for cancer.

If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes, they suggested.  

“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” co-senior author Hans Van Dongen, PhD, a professor at Washington State University in Pullman and director of the WSU Sleep and Performance Research Center, Spokane, said in a statement. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”

The study was supported by start-up funds from Washington State University and a Center for Human Health and the Environment grant from North Carolina State University, and in part by the United States Army Medical Research and Development Command, the National Institutes of Health, CDMRP (Congressionally Directed Medical Research Programs) Peer Reviewed Cancer Research Program award, and the BRAVE investment.

The authors have disclosed no relevant financial relationships.

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

Working night shifts has been associated with an increased risk for certain cancers, as well as other health disorders. Indeed, the World Health Organization’s International Agency for Research on Cancer (IARC) has classified night shift work as “probably carcinogenic to humans.”

But why night shift should elevate the risk for cancer has been unclear.

A new study shows that a simulated night shift schedule significantly altered the normal circadian rhythmicity of genes that are involved in cancer hallmark pathways. It also found that this circadian misalignment caused circadian dysregulation of genes involved in key DNA repair pathways.

“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s biological sciences division in Richland, Wash.

The study was published online in the Journal of Pineal Research.
 

Study conducted among volunteers 

The study was carried out among healthy volunteers who were subjected to simulated night shift or day shift schedules.

The cohort comprised 14 adults between the ages of 22 and 34 years who had normal nighttime sleep schedules. They were randomly assigned (seven in each group) to a simulated day shift schedule that involved 3 days of daytime wakefulness (6 a.m.-10 p.m.), or a simulated night shift schedule involving 3 days of nighttime wakefulness (6 p.m.-10 a.m.).

After the 3 days of simulated shift work, all participants were then kept in a constant routine protocol (used to study humans’ internally generated biological rhythms independent of any external influences). As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under laboratory conditions with constant light exposure and room temperature and evenly distributed food intake (hourly isocaloric snacks).

Blood samples were collected at 3-hour intervals and used for leukocyte transcriptome analysis and DNA damage assessment.

The authors found that the circadian expression of canonical clock genes was substantially altered by the simulated night shift schedule vs. the day shift schedule. Four genes (CRY1, CRY2, PER2, and NR1D2) lost their normal day-shift rhythmicity following the night shift schedule, and NPAS2 gene expression was not rhythmic during the day shift but exhibited circadian rhythmicity in the simulated night shift condition. Three other genes (NR1D1, PER3, and DBP) were significantly rhythmic during both shifts.

The team also looked at the effect of night shift on circadian rhythmicity in cancer hallmark genes, using a panel of 726 genes. The analysis showed that:

• 257 (35.4%) were rhythmic after at least one of the two simulated shift work conditions.
• 113 (15.6%) were rhythmic in day shift only.
• 96 (13.2%) were rhythmic during night shift only.
• 48 (6.6%) were rhythmic during both shifts.

A subset of 10 (1.4%) genes exhibited a significant phase advance (3.7 to 8.3 hours) or phase delay (2.8 to 7.0 hours) during the night shift vs. the day shift.

Thus, the authors concluded, shift work caused significant disturbances in the rhythmicity of gene expression in cancer hallmark pathways.

Findings also showed that night shift work increases endogenous and exogenous DNA damage. Endogenous DNA damage was generally higher after the night shift compared to the day shift, and across the 24-hour constant routine the percentage of cells with BRCA1 and g H2AX foci was significantly higher for night shift.
 

Next steps

The team said that the next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk for cancer.

If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes, they suggested.  

“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” co-senior author Hans Van Dongen, PhD, a professor at Washington State University in Pullman and director of the WSU Sleep and Performance Research Center, Spokane, said in a statement. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”

The study was supported by start-up funds from Washington State University and a Center for Human Health and the Environment grant from North Carolina State University, and in part by the United States Army Medical Research and Development Command, the National Institutes of Health, CDMRP (Congressionally Directed Medical Research Programs) Peer Reviewed Cancer Research Program award, and the BRAVE investment.

The authors have disclosed no relevant financial relationships.

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

Specialty palliative care interventions improve outcomes in patients with hematologic malignancies but are underutilized, according to findings from a systematic literature review.

Outcomes that were improved, as demonstrated by 16 studies that met inclusion criteria for the review, included symptom management, inpatient mortality, health care utilization, health care costs, and caregiver-reported outcomes, Elizabeth Elliott, DO, a hematology and oncology fellow at the Cardinal Bernardin Cancer Center, Loyola University, Maywood, Ill., and colleagues reported.

The findings were published online in the Journal of Pain and Symptom Management.
 

Palliative care needs

Patients with hematologic malignancies, including leukemia, myeloma, and lymphoma, have a high need for supportive care, the authors noted, adding that, although its use has increased over time, palliative care (PC) is often provided late in the disease course – sometimes only in the final days of life.

“Compared with their solid tumor counterparts, patients with hematologic malignancies experience higher symptom burdens, have higher rates of cancer-directed care near death, and are more likely to die while hospitalized than at home or in hospice,” they wrote. “Despite this need, specialist palliative care is less commonly utilized in patients with hematologic malignancies than other cancer types.”

Given the high health care utilization among patients with hematologic malignancies, earlier and more widespread utilization of PC in this population may significantly reduce health care costs, they added.
 

Palliative care benefits

Of 5,345 studies published between 2005 and 2020 and screened for the current review, 16 met inclusion criteria, including 10 retrospective cohort studies; 4 prospective cohort studies; and 2 randomized, controlled studies.

Nine studies included only patients with hematologic malignancies and seven included both patients with solid tumors and patients with hematologic malignancies. Each study assessed as being of moderate quality.

Benefits of PC as demonstrated in the studies included:

Symptom management: One study, for example, showed that an integrated psychological and PC intervention improved traumatic stress levels, degree and number of physical symptoms, pain intensity, depressive symptoms, and quality of life, compared with no intervention. Another showed that the percentage of patients reporting moderate to severe pain improved from 57% to 18% with a PC intervention, and the number reporting depressive episodes improved from 13% to 5%.

Reduced in-patient death: Findings from eight studies showed that 21.9%-83% of those receiving PC died at home, compared with 6.0%-8.9% of controls. Two studies showed that PC provided at least 20 days prior to death decreased the likelihood of inpatient death and death in an ICU, compared with controls, and one showed that the rate of in-hospital deaths was 30% for those with home PC or hospice, compared with 80% of controls.

Health care utilization: The studies showed that hospitalization occurred in 45%-76.3% of hematologic malignancy patients who received PC, compared with 98% of controls. The odds ratio for hospitalization among acute leukemia patients receiving PC was 0.64, compared with 2.53 among those in a historical control group.

Caregiver-reported outcomes: One randomized, controlled study showed that PC was associated with smaller increases in depression scores, improved coping, and improved scores in multiple quality of life domains in caregivers versus controls.

Survival: One study showed that a larger percentage of hematologic malignancy patients who died 1-6 months after diagnosis had not received PC (28% vs. 23%), whereas more of those who died 6-12 months or 12 or more months after diagnosis had received PC (23.9 vs. 14.9% and 42.5% vs. 22.0%).

Health care costs: Two studies showed a decrease in inpatient costs after a palliative care consultation. Decreases in hospitalization costs were $2,321 and $1,506 for less medically complex patients and $3,515 and $5,617 for more medically complex patient.

Improving PC utilization

One potential strategy to promote earlier referrals to PC is improved education for hematologists, the authors said, citing a study showing that 98% of oncology fellows at one center reported improvement in their ability to assess and manage patient symptoms after completion of a 4-week mandatory PC rotation.

“Another strategy to improve referrals to PC of hematologic malignancies patients could be the creation of programs which facilitate collaboration between PC providers and hematologists, such as the palliative and supportive care special interest group within the American Society for Transplantation and Cellular Therapy,” they wrote.

A third strategy “could be to provide a concurrent care model, in which cancer directed therapy (such as transfusions) is provided at the same time as hospice care,” they added, explaining that such an approach was shown in a study of patients with advanced non–small cell lung cancer to be associated with less aggressive medical treatment and lower costs.

The authors also stressed that patient with solid tumors and those with hematologic malignancies have differing supportive care needs and health care utilization, but several studies included in the current review included both types of cancer.

“Further studies investigating PC use exclusively in patients with hematologic malignancies are needed. Our results demonstrate a strong argument for hematologists to refer their patients early and often for specialized PC,” they concluded.

Indeed, when PC is integrated within hematologic malignancies, impacts occur that are similar to those seen in a variety of other diseases and include improved symptom control, enhanced caregiver experience, and reduced burdens on the health care system, Toby C Campbell, MD, said in an interview.

“The benefits of providing palliative care concurrent with standard cancer care is felt by all the major stakeholders in this care: the patients, their caregivers, and the health care system around them,” said Dr. Campbell, a thoracic medical oncologist and professor in the division of hematology, medical oncology, and palliative care at the University of Wisconsin–Madison.
 

Overcoming challenges

However, this is “new territory” for most programs, added Dr. Campbell, who also is the University of Wisconsin health chief of palliative care and holds the Ellen and Peter O. Johnson Chair in Palliative Care .

“The palliative care clinicians have a lot of learning to do if they’re going to enter this space and provide expert care,” he said, adding that expert care is what is needed and what was studied in this review. “Providing palliative care to patients with hematologic malignancies has a unique pace and a number of subspecialized therapeutic options with which the palliative care clinician must become familiar.”

Examples include bone marrow transplantation with prolonged hospitalizations and transfusion support, he said.

“Palliative care programs, in order to provide high quality care, will need to familiarize themselves with these therapies and develop close partnership with hematologists to integrate seamlessly into the patient’s care,” he added. “At some centers, culture changes will be necessary concurrent with the clinical practice change of integrating palliative care and it is the responsibility of the palliative care clinicians to bring their very best to these new relationships and patient populations.”

The authors reported having no disclosures. Dr. Campbell also reported having no disclosures.

[email protected]

Specialty palliative care interventions improve outcomes in patients with hematologic malignancies but are underutilized, according to findings from a systematic literature review.

Outcomes that were improved, as demonstrated by 16 studies that met inclusion criteria for the review, included symptom management, inpatient mortality, health care utilization, health care costs, and caregiver-reported outcomes, Elizabeth Elliott, DO, a hematology and oncology fellow at the Cardinal Bernardin Cancer Center, Loyola University, Maywood, Ill., and colleagues reported.

The findings were published online in the Journal of Pain and Symptom Management.
 

Palliative care needs

Patients with hematologic malignancies, including leukemia, myeloma, and lymphoma, have a high need for supportive care, the authors noted, adding that, although its use has increased over time, palliative care (PC) is often provided late in the disease course – sometimes only in the final days of life.

“Compared with their solid tumor counterparts, patients with hematologic malignancies experience higher symptom burdens, have higher rates of cancer-directed care near death, and are more likely to die while hospitalized than at home or in hospice,” they wrote. “Despite this need, specialist palliative care is less commonly utilized in patients with hematologic malignancies than other cancer types.”

Given the high health care utilization among patients with hematologic malignancies, earlier and more widespread utilization of PC in this population may significantly reduce health care costs, they added.
 

Palliative care benefits

Of 5,345 studies published between 2005 and 2020 and screened for the current review, 16 met inclusion criteria, including 10 retrospective cohort studies; 4 prospective cohort studies; and 2 randomized, controlled studies.

Nine studies included only patients with hematologic malignancies and seven included both patients with solid tumors and patients with hematologic malignancies. Each study assessed as being of moderate quality.

Benefits of PC as demonstrated in the studies included:

Symptom management: One study, for example, showed that an integrated psychological and PC intervention improved traumatic stress levels, degree and number of physical symptoms, pain intensity, depressive symptoms, and quality of life, compared with no intervention. Another showed that the percentage of patients reporting moderate to severe pain improved from 57% to 18% with a PC intervention, and the number reporting depressive episodes improved from 13% to 5%.

Reduced in-patient death: Findings from eight studies showed that 21.9%-83% of those receiving PC died at home, compared with 6.0%-8.9% of controls. Two studies showed that PC provided at least 20 days prior to death decreased the likelihood of inpatient death and death in an ICU, compared with controls, and one showed that the rate of in-hospital deaths was 30% for those with home PC or hospice, compared with 80% of controls.

Health care utilization: The studies showed that hospitalization occurred in 45%-76.3% of hematologic malignancy patients who received PC, compared with 98% of controls. The odds ratio for hospitalization among acute leukemia patients receiving PC was 0.64, compared with 2.53 among those in a historical control group.

Caregiver-reported outcomes: One randomized, controlled study showed that PC was associated with smaller increases in depression scores, improved coping, and improved scores in multiple quality of life domains in caregivers versus controls.

Survival: One study showed that a larger percentage of hematologic malignancy patients who died 1-6 months after diagnosis had not received PC (28% vs. 23%), whereas more of those who died 6-12 months or 12 or more months after diagnosis had received PC (23.9 vs. 14.9% and 42.5% vs. 22.0%).

Health care costs: Two studies showed a decrease in inpatient costs after a palliative care consultation. Decreases in hospitalization costs were $2,321 and $1,506 for less medically complex patients and $3,515 and $5,617 for more medically complex patient.

Improving PC utilization

One potential strategy to promote earlier referrals to PC is improved education for hematologists, the authors said, citing a study showing that 98% of oncology fellows at one center reported improvement in their ability to assess and manage patient symptoms after completion of a 4-week mandatory PC rotation.

“Another strategy to improve referrals to PC of hematologic malignancies patients could be the creation of programs which facilitate collaboration between PC providers and hematologists, such as the palliative and supportive care special interest group within the American Society for Transplantation and Cellular Therapy,” they wrote.

A third strategy “could be to provide a concurrent care model, in which cancer directed therapy (such as transfusions) is provided at the same time as hospice care,” they added, explaining that such an approach was shown in a study of patients with advanced non–small cell lung cancer to be associated with less aggressive medical treatment and lower costs.

The authors also stressed that patient with solid tumors and those with hematologic malignancies have differing supportive care needs and health care utilization, but several studies included in the current review included both types of cancer.

“Further studies investigating PC use exclusively in patients with hematologic malignancies are needed. Our results demonstrate a strong argument for hematologists to refer their patients early and often for specialized PC,” they concluded.

Indeed, when PC is integrated within hematologic malignancies, impacts occur that are similar to those seen in a variety of other diseases and include improved symptom control, enhanced caregiver experience, and reduced burdens on the health care system, Toby C Campbell, MD, said in an interview.

“The benefits of providing palliative care concurrent with standard cancer care is felt by all the major stakeholders in this care: the patients, their caregivers, and the health care system around them,” said Dr. Campbell, a thoracic medical oncologist and professor in the division of hematology, medical oncology, and palliative care at the University of Wisconsin–Madison.
 

Overcoming challenges

However, this is “new territory” for most programs, added Dr. Campbell, who also is the University of Wisconsin health chief of palliative care and holds the Ellen and Peter O. Johnson Chair in Palliative Care .

“The palliative care clinicians have a lot of learning to do if they’re going to enter this space and provide expert care,” he said, adding that expert care is what is needed and what was studied in this review. “Providing palliative care to patients with hematologic malignancies has a unique pace and a number of subspecialized therapeutic options with which the palliative care clinician must become familiar.”

Examples include bone marrow transplantation with prolonged hospitalizations and transfusion support, he said.

“Palliative care programs, in order to provide high quality care, will need to familiarize themselves with these therapies and develop close partnership with hematologists to integrate seamlessly into the patient’s care,” he added. “At some centers, culture changes will be necessary concurrent with the clinical practice change of integrating palliative care and it is the responsibility of the palliative care clinicians to bring their very best to these new relationships and patient populations.”

The authors reported having no disclosures. Dr. Campbell also reported having no disclosures.

[email protected]

Specialty palliative care interventions improve outcomes in patients with hematologic malignancies but are underutilized, according to findings from a systematic literature review.

Outcomes that were improved, as demonstrated by 16 studies that met inclusion criteria for the review, included symptom management, inpatient mortality, health care utilization, health care costs, and caregiver-reported outcomes, Elizabeth Elliott, DO, a hematology and oncology fellow at the Cardinal Bernardin Cancer Center, Loyola University, Maywood, Ill., and colleagues reported.

The findings were published online in the Journal of Pain and Symptom Management.
 

Palliative care needs

Patients with hematologic malignancies, including leukemia, myeloma, and lymphoma, have a high need for supportive care, the authors noted, adding that, although its use has increased over time, palliative care (PC) is often provided late in the disease course – sometimes only in the final days of life.

“Compared with their solid tumor counterparts, patients with hematologic malignancies experience higher symptom burdens, have higher rates of cancer-directed care near death, and are more likely to die while hospitalized than at home or in hospice,” they wrote. “Despite this need, specialist palliative care is less commonly utilized in patients with hematologic malignancies than other cancer types.”

Given the high health care utilization among patients with hematologic malignancies, earlier and more widespread utilization of PC in this population may significantly reduce health care costs, they added.
 

Palliative care benefits

Of 5,345 studies published between 2005 and 2020 and screened for the current review, 16 met inclusion criteria, including 10 retrospective cohort studies; 4 prospective cohort studies; and 2 randomized, controlled studies.

Nine studies included only patients with hematologic malignancies and seven included both patients with solid tumors and patients with hematologic malignancies. Each study assessed as being of moderate quality.

Benefits of PC as demonstrated in the studies included:

Symptom management: One study, for example, showed that an integrated psychological and PC intervention improved traumatic stress levels, degree and number of physical symptoms, pain intensity, depressive symptoms, and quality of life, compared with no intervention. Another showed that the percentage of patients reporting moderate to severe pain improved from 57% to 18% with a PC intervention, and the number reporting depressive episodes improved from 13% to 5%.

Reduced in-patient death: Findings from eight studies showed that 21.9%-83% of those receiving PC died at home, compared with 6.0%-8.9% of controls. Two studies showed that PC provided at least 20 days prior to death decreased the likelihood of inpatient death and death in an ICU, compared with controls, and one showed that the rate of in-hospital deaths was 30% for those with home PC or hospice, compared with 80% of controls.

Health care utilization: The studies showed that hospitalization occurred in 45%-76.3% of hematologic malignancy patients who received PC, compared with 98% of controls. The odds ratio for hospitalization among acute leukemia patients receiving PC was 0.64, compared with 2.53 among those in a historical control group.

Caregiver-reported outcomes: One randomized, controlled study showed that PC was associated with smaller increases in depression scores, improved coping, and improved scores in multiple quality of life domains in caregivers versus controls.

Survival: One study showed that a larger percentage of hematologic malignancy patients who died 1-6 months after diagnosis had not received PC (28% vs. 23%), whereas more of those who died 6-12 months or 12 or more months after diagnosis had received PC (23.9 vs. 14.9% and 42.5% vs. 22.0%).

Health care costs: Two studies showed a decrease in inpatient costs after a palliative care consultation. Decreases in hospitalization costs were $2,321 and $1,506 for less medically complex patients and $3,515 and $5,617 for more medically complex patient.

Improving PC utilization

One potential strategy to promote earlier referrals to PC is improved education for hematologists, the authors said, citing a study showing that 98% of oncology fellows at one center reported improvement in their ability to assess and manage patient symptoms after completion of a 4-week mandatory PC rotation.

“Another strategy to improve referrals to PC of hematologic malignancies patients could be the creation of programs which facilitate collaboration between PC providers and hematologists, such as the palliative and supportive care special interest group within the American Society for Transplantation and Cellular Therapy,” they wrote.

A third strategy “could be to provide a concurrent care model, in which cancer directed therapy (such as transfusions) is provided at the same time as hospice care,” they added, explaining that such an approach was shown in a study of patients with advanced non–small cell lung cancer to be associated with less aggressive medical treatment and lower costs.

The authors also stressed that patient with solid tumors and those with hematologic malignancies have differing supportive care needs and health care utilization, but several studies included in the current review included both types of cancer.

“Further studies investigating PC use exclusively in patients with hematologic malignancies are needed. Our results demonstrate a strong argument for hematologists to refer their patients early and often for specialized PC,” they concluded.

Indeed, when PC is integrated within hematologic malignancies, impacts occur that are similar to those seen in a variety of other diseases and include improved symptom control, enhanced caregiver experience, and reduced burdens on the health care system, Toby C Campbell, MD, said in an interview.

“The benefits of providing palliative care concurrent with standard cancer care is felt by all the major stakeholders in this care: the patients, their caregivers, and the health care system around them,” said Dr. Campbell, a thoracic medical oncologist and professor in the division of hematology, medical oncology, and palliative care at the University of Wisconsin–Madison.
 

Overcoming challenges

However, this is “new territory” for most programs, added Dr. Campbell, who also is the University of Wisconsin health chief of palliative care and holds the Ellen and Peter O. Johnson Chair in Palliative Care .

“The palliative care clinicians have a lot of learning to do if they’re going to enter this space and provide expert care,” he said, adding that expert care is what is needed and what was studied in this review. “Providing palliative care to patients with hematologic malignancies has a unique pace and a number of subspecialized therapeutic options with which the palliative care clinician must become familiar.”

Examples include bone marrow transplantation with prolonged hospitalizations and transfusion support, he said.

“Palliative care programs, in order to provide high quality care, will need to familiarize themselves with these therapies and develop close partnership with hematologists to integrate seamlessly into the patient’s care,” he added. “At some centers, culture changes will be necessary concurrent with the clinical practice change of integrating palliative care and it is the responsibility of the palliative care clinicians to bring their very best to these new relationships and patient populations.”

The authors reported having no disclosures. Dr. Campbell also reported having no disclosures.

[email protected]

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

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

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

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

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

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

Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices. New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

Courtesy Dr. Marcela Ferrada

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institutes of Health, Bethesda, Md. The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

VEXAS is an acronym for:

• Vacuoles in bone marrow cells
• E-1 activating enzyme, which is what UBA1 encodes for
• X-linked
• Autoinflammatory
• Somatic mutation featuring hematologic mosaicism

Dr. Beck said that VEXAS is “probably affecting thousands of Americans,” but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.
 

A new way of looking for disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Dr. Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease – that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes that might explain the shared patient symptoms – the investigators took a genotype-first approach. They scanned the mapped genomic sequences of patients in the National Institutes of Health Undiagnosed Diseases Network, which led them to zero in on mutations in UBA1 as their top candidate.

“We targeted the ubiquitin-proteasome pathway, because it has been implicated in many autoinflammatory diseases – for example, HA20 [A20 haploinsufficiency] and CANDLE syndrome [Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature]. Many of these recurrent inflammatory diseases are caused by mutations within this pathway,” Dr. Beck said in an interview.

Next, they analyzed the genomes of patients in other NIH databases and patients from other study populations at the University College London and Leeds Teaching Hospitals NHS Trust in the United Kingdom in a search for UBA1 somatic mutations, eventually identifying 25 men with the shared features they called VEXAS. These 25 formed the basis for their initial report on the syndrome in the New England Journal of Medicine.

Most autoinflammatory diseases appear in childhood because they stem from germline mutations. VEXAS syndrome, because of somatic mutations with mosaicism, appears to manifest later in life: The median age of the initial 25-man cohort was 64 years, ranging from 45 to 80 years. It’s a severe disorder. By the time the investigators were preparing their paper for publication, 10 of the 25 patients, or 40%, had died.

“I think that somatic mutations may account for a significant percentage of severe. adult-onset rheumatologic diseases, and it may change the way we think about treating them based on having a genetic diagnosis,” Dr. Beck said.

“This approach could be expanded to look at other pathways we know are important in inflammation, or alternatively, it could be completely unbiased and look for any shared variation that occurs across undiagnosed patients with inflammatory diseases. I think that one thing that’s important about our study is that previously we had been looking for mutations that really in most cases were the same sort of germline mutations present in [pediatric] patients who have disease at early onset, but now we’re thinking about things differently. There may be a different type of genetics that drives adult-onset rheumatologic disease, and this would be somatic mutations which are not present in every cell of the body, just in the blood, and that’s why there’s just this blood-based disease.”
 

When to suspect VEXAS syndrome

Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.

Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.

Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center

Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers ([email protected]).

In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.

Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.

Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.

First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.

Courtesy Dr. Marcela Ferrada

Myelodysplastic syndrome and hematologic abnormalities

While patients with both myelodysplastic syndrome and relapsing polychondritis have been known in the literature for many years, it’s not until now that researchers are seeing a connection between the two, Dr. Ferrada said.

A majority of the VEXAS patients in the NEJM study had a workup for myelodysplastic syndrome, but only 24% met criteria. However, many were within the spectrum of myelodysplastic disease and some did not meet criteria because their anemia was attributed to a rheumatologic diagnosis and they did not have a known genetic driver of myelodysplastic syndrome, Dr. Beck said. It also fits with this new evidence that UBA1 is probably a driver of myelodysplastic syndrome in and of itself, and that anemia and hematologic involvement are not secondary to the rheumatologic disease; they are linked to the same disease process.

Dr. Beck said that there may be a subset of patients who present with primarily hematologic manifestations, noting the NEJM study could have ascertainment bias because the researchers analyzed mainly patients presenting to their clinic with relapsing polychondritis and severe inflammation. NIH researchers also are still looking in their cohort for any association with hematologic malignancies that preceded clinical manifestations, he said.
 

More cases reported

As of early April, another 27 cases had been reported in the literature as more researchers have begun to look for patients with UBA1 mutations, some with additional presenting clinical features associated with VEXAS, including chronic progressive inflammatory arthritis, Kikuchi-Fujimoto disease, spondyloarthritis, and bacterial pneumonia.

“Many times with rare diseases, we can’t get enough patients to understand the full spectrum of the disease, but this disease seems to be far more common than we would have expected. We’re actually getting many referrals,” Dr. Beck said.

It appears so far that the range of somatic UBA1 mutations that have been discovered in VEXAS patients does make a difference in the severity of clinical presentation and could potentially be useful in prognosis, Dr. Beck said.

Right now, NIH researchers are asking patients about their natural clinical course, assessing disease activity, and determining which treatments get a response, with the ultimate goal of a treatment trial at the NIH.

Treatment

Developing better treatments for VEXAS syndrome is a priority. In the initial report on VEXAS, the researchers found that the only reliably effective therapy is high-dose corticosteroids. Dr. Ferrada said that NIH investigators have begun thinking about agents that target both the hematologic and inflammatory features of VEXAS. “Most patients get exposed to treatments that are targeted to decrease the inflammatory process, and some of these treatments help partially but not completely to decrease the amount of steroids that patients are taking. For example, one of the medications is tocilizumab. [It was used in] patients who had previous diagnosis of relapsing polychondritis, but they still had to take steroids and their hematologic manifestations keep progressing. We’re in the process of figuring out medications that may help in treating both.” Dr. Ferrada added that because the source of the mutation is in the bone marrow, transplantation may be an effective option.

Laboratory work to identify potential treatments for VEXAS in studies of model organisms could identify treatments outside of the classic anti-inflammatory agents, such as targeting certain cell types in the bone marrow or the ubiquitin-proteasome pathway, Dr. Beck said. “We think that however UBA1 works to initiate inflammation may be important not just in VEXAS but in other diseases. Rare diseases may be informing the mechanisms in common diseases.”

The VEXAS NEJM study was sponsored by the NIH Intramural Research Programs and by an EU Horizon 2020 Research and Innovation Program grant. Dr. Beck reported a patent pending on “Diagnosis and Treatment of VEXAS with Mosaic Missense Mutations in UBA1.”

[email protected]

Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices. New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

Courtesy Dr. Marcela Ferrada

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institutes of Health, Bethesda, Md. The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

VEXAS is an acronym for:

• Vacuoles in bone marrow cells
• E-1 activating enzyme, which is what UBA1 encodes for
• X-linked
• Autoinflammatory
• Somatic mutation featuring hematologic mosaicism

Dr. Beck said that VEXAS is “probably affecting thousands of Americans,” but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.
 

A new way of looking for disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Dr. Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease – that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes that might explain the shared patient symptoms – the investigators took a genotype-first approach. They scanned the mapped genomic sequences of patients in the National Institutes of Health Undiagnosed Diseases Network, which led them to zero in on mutations in UBA1 as their top candidate.

“We targeted the ubiquitin-proteasome pathway, because it has been implicated in many autoinflammatory diseases – for example, HA20 [A20 haploinsufficiency] and CANDLE syndrome [Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature]. Many of these recurrent inflammatory diseases are caused by mutations within this pathway,” Dr. Beck said in an interview.

Next, they analyzed the genomes of patients in other NIH databases and patients from other study populations at the University College London and Leeds Teaching Hospitals NHS Trust in the United Kingdom in a search for UBA1 somatic mutations, eventually identifying 25 men with the shared features they called VEXAS. These 25 formed the basis for their initial report on the syndrome in the New England Journal of Medicine.

Most autoinflammatory diseases appear in childhood because they stem from germline mutations. VEXAS syndrome, because of somatic mutations with mosaicism, appears to manifest later in life: The median age of the initial 25-man cohort was 64 years, ranging from 45 to 80 years. It’s a severe disorder. By the time the investigators were preparing their paper for publication, 10 of the 25 patients, or 40%, had died.

“I think that somatic mutations may account for a significant percentage of severe. adult-onset rheumatologic diseases, and it may change the way we think about treating them based on having a genetic diagnosis,” Dr. Beck said.

“This approach could be expanded to look at other pathways we know are important in inflammation, or alternatively, it could be completely unbiased and look for any shared variation that occurs across undiagnosed patients with inflammatory diseases. I think that one thing that’s important about our study is that previously we had been looking for mutations that really in most cases were the same sort of germline mutations present in [pediatric] patients who have disease at early onset, but now we’re thinking about things differently. There may be a different type of genetics that drives adult-onset rheumatologic disease, and this would be somatic mutations which are not present in every cell of the body, just in the blood, and that’s why there’s just this blood-based disease.”
 

When to suspect VEXAS syndrome

Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.

Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.

Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center

Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers ([email protected]).

In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.

Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.

Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.

First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.

Courtesy Dr. Marcela Ferrada

Myelodysplastic syndrome and hematologic abnormalities

While patients with both myelodysplastic syndrome and relapsing polychondritis have been known in the literature for many years, it’s not until now that researchers are seeing a connection between the two, Dr. Ferrada said.

A majority of the VEXAS patients in the NEJM study had a workup for myelodysplastic syndrome, but only 24% met criteria. However, many were within the spectrum of myelodysplastic disease and some did not meet criteria because their anemia was attributed to a rheumatologic diagnosis and they did not have a known genetic driver of myelodysplastic syndrome, Dr. Beck said. It also fits with this new evidence that UBA1 is probably a driver of myelodysplastic syndrome in and of itself, and that anemia and hematologic involvement are not secondary to the rheumatologic disease; they are linked to the same disease process.

Dr. Beck said that there may be a subset of patients who present with primarily hematologic manifestations, noting the NEJM study could have ascertainment bias because the researchers analyzed mainly patients presenting to their clinic with relapsing polychondritis and severe inflammation. NIH researchers also are still looking in their cohort for any association with hematologic malignancies that preceded clinical manifestations, he said.
 

More cases reported

As of early April, another 27 cases had been reported in the literature as more researchers have begun to look for patients with UBA1 mutations, some with additional presenting clinical features associated with VEXAS, including chronic progressive inflammatory arthritis, Kikuchi-Fujimoto disease, spondyloarthritis, and bacterial pneumonia.

“Many times with rare diseases, we can’t get enough patients to understand the full spectrum of the disease, but this disease seems to be far more common than we would have expected. We’re actually getting many referrals,” Dr. Beck said.

It appears so far that the range of somatic UBA1 mutations that have been discovered in VEXAS patients does make a difference in the severity of clinical presentation and could potentially be useful in prognosis, Dr. Beck said.

Right now, NIH researchers are asking patients about their natural clinical course, assessing disease activity, and determining which treatments get a response, with the ultimate goal of a treatment trial at the NIH.

Treatment

Developing better treatments for VEXAS syndrome is a priority. In the initial report on VEXAS, the researchers found that the only reliably effective therapy is high-dose corticosteroids. Dr. Ferrada said that NIH investigators have begun thinking about agents that target both the hematologic and inflammatory features of VEXAS. “Most patients get exposed to treatments that are targeted to decrease the inflammatory process, and some of these treatments help partially but not completely to decrease the amount of steroids that patients are taking. For example, one of the medications is tocilizumab. [It was used in] patients who had previous diagnosis of relapsing polychondritis, but they still had to take steroids and their hematologic manifestations keep progressing. We’re in the process of figuring out medications that may help in treating both.” Dr. Ferrada added that because the source of the mutation is in the bone marrow, transplantation may be an effective option.

Laboratory work to identify potential treatments for VEXAS in studies of model organisms could identify treatments outside of the classic anti-inflammatory agents, such as targeting certain cell types in the bone marrow or the ubiquitin-proteasome pathway, Dr. Beck said. “We think that however UBA1 works to initiate inflammation may be important not just in VEXAS but in other diseases. Rare diseases may be informing the mechanisms in common diseases.”

The VEXAS NEJM study was sponsored by the NIH Intramural Research Programs and by an EU Horizon 2020 Research and Innovation Program grant. Dr. Beck reported a patent pending on “Diagnosis and Treatment of VEXAS with Mosaic Missense Mutations in UBA1.”

[email protected]

Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices. New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

Courtesy Dr. Marcela Ferrada

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institutes of Health, Bethesda, Md. The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

VEXAS is an acronym for:

• Vacuoles in bone marrow cells
• E-1 activating enzyme, which is what UBA1 encodes for
• X-linked
• Autoinflammatory
• Somatic mutation featuring hematologic mosaicism

Dr. Beck said that VEXAS is “probably affecting thousands of Americans,” but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.
 

A new way of looking for disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Dr. Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease – that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes that might explain the shared patient symptoms – the investigators took a genotype-first approach. They scanned the mapped genomic sequences of patients in the National Institutes of Health Undiagnosed Diseases Network, which led them to zero in on mutations in UBA1 as their top candidate.

“We targeted the ubiquitin-proteasome pathway, because it has been implicated in many autoinflammatory diseases – for example, HA20 [A20 haploinsufficiency] and CANDLE syndrome [Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature]. Many of these recurrent inflammatory diseases are caused by mutations within this pathway,” Dr. Beck said in an interview.

Next, they analyzed the genomes of patients in other NIH databases and patients from other study populations at the University College London and Leeds Teaching Hospitals NHS Trust in the United Kingdom in a search for UBA1 somatic mutations, eventually identifying 25 men with the shared features they called VEXAS. These 25 formed the basis for their initial report on the syndrome in the New England Journal of Medicine.

Most autoinflammatory diseases appear in childhood because they stem from germline mutations. VEXAS syndrome, because of somatic mutations with mosaicism, appears to manifest later in life: The median age of the initial 25-man cohort was 64 years, ranging from 45 to 80 years. It’s a severe disorder. By the time the investigators were preparing their paper for publication, 10 of the 25 patients, or 40%, had died.

“I think that somatic mutations may account for a significant percentage of severe. adult-onset rheumatologic diseases, and it may change the way we think about treating them based on having a genetic diagnosis,” Dr. Beck said.

“This approach could be expanded to look at other pathways we know are important in inflammation, or alternatively, it could be completely unbiased and look for any shared variation that occurs across undiagnosed patients with inflammatory diseases. I think that one thing that’s important about our study is that previously we had been looking for mutations that really in most cases were the same sort of germline mutations present in [pediatric] patients who have disease at early onset, but now we’re thinking about things differently. There may be a different type of genetics that drives adult-onset rheumatologic disease, and this would be somatic mutations which are not present in every cell of the body, just in the blood, and that’s why there’s just this blood-based disease.”
 

When to suspect VEXAS syndrome

Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.

Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.

Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center

Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers ([email protected]).

In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.

Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.

Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.

First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.

Courtesy Dr. Marcela Ferrada

Myelodysplastic syndrome and hematologic abnormalities

While patients with both myelodysplastic syndrome and relapsing polychondritis have been known in the literature for many years, it’s not until now that researchers are seeing a connection between the two, Dr. Ferrada said.

A majority of the VEXAS patients in the NEJM study had a workup for myelodysplastic syndrome, but only 24% met criteria. However, many were within the spectrum of myelodysplastic disease and some did not meet criteria because their anemia was attributed to a rheumatologic diagnosis and they did not have a known genetic driver of myelodysplastic syndrome, Dr. Beck said. It also fits with this new evidence that UBA1 is probably a driver of myelodysplastic syndrome in and of itself, and that anemia and hematologic involvement are not secondary to the rheumatologic disease; they are linked to the same disease process.

Dr. Beck said that there may be a subset of patients who present with primarily hematologic manifestations, noting the NEJM study could have ascertainment bias because the researchers analyzed mainly patients presenting to their clinic with relapsing polychondritis and severe inflammation. NIH researchers also are still looking in their cohort for any association with hematologic malignancies that preceded clinical manifestations, he said.
 

More cases reported

As of early April, another 27 cases had been reported in the literature as more researchers have begun to look for patients with UBA1 mutations, some with additional presenting clinical features associated with VEXAS, including chronic progressive inflammatory arthritis, Kikuchi-Fujimoto disease, spondyloarthritis, and bacterial pneumonia.

“Many times with rare diseases, we can’t get enough patients to understand the full spectrum of the disease, but this disease seems to be far more common than we would have expected. We’re actually getting many referrals,” Dr. Beck said.

It appears so far that the range of somatic UBA1 mutations that have been discovered in VEXAS patients does make a difference in the severity of clinical presentation and could potentially be useful in prognosis, Dr. Beck said.

Right now, NIH researchers are asking patients about their natural clinical course, assessing disease activity, and determining which treatments get a response, with the ultimate goal of a treatment trial at the NIH.

Treatment

Developing better treatments for VEXAS syndrome is a priority. In the initial report on VEXAS, the researchers found that the only reliably effective therapy is high-dose corticosteroids. Dr. Ferrada said that NIH investigators have begun thinking about agents that target both the hematologic and inflammatory features of VEXAS. “Most patients get exposed to treatments that are targeted to decrease the inflammatory process, and some of these treatments help partially but not completely to decrease the amount of steroids that patients are taking. For example, one of the medications is tocilizumab. [It was used in] patients who had previous diagnosis of relapsing polychondritis, but they still had to take steroids and their hematologic manifestations keep progressing. We’re in the process of figuring out medications that may help in treating both.” Dr. Ferrada added that because the source of the mutation is in the bone marrow, transplantation may be an effective option.

Laboratory work to identify potential treatments for VEXAS in studies of model organisms could identify treatments outside of the classic anti-inflammatory agents, such as targeting certain cell types in the bone marrow or the ubiquitin-proteasome pathway, Dr. Beck said. “We think that however UBA1 works to initiate inflammation may be important not just in VEXAS but in other diseases. Rare diseases may be informing the mechanisms in common diseases.”

The VEXAS NEJM study was sponsored by the NIH Intramural Research Programs and by an EU Horizon 2020 Research and Innovation Program grant. Dr. Beck reported a patent pending on “Diagnosis and Treatment of VEXAS with Mosaic Missense Mutations in UBA1.”

[email protected]

Patients at very high risk for melanoma, including those with a family history or with inherited pathogenic variants of genes that increase the risk, likely benefit from routine whole-body screening for melanoma and education about UV protection.

Those are key findings from the first prospective cohort study to quantify the benefit of screening in melanoma-prone families, which was published online April 2 in Cancer Epidemiology, Biomarkers & Prevention.

“Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma, which includes people from melanoma-prone families (at least two relatives who have had melanoma) and those with inherited pathogenic gene variants of the CDKN2A or CDK4 genes, which increase risk for melanoma,” lead author Michael R. Sargen, MD, said in an interview. “In our study, we investigated whether screening and educational interventions, including education about the appearance of melanoma and strategies for protecting skin from ultraviolet damage, contributed to early diagnosis of melanoma in individuals from melanoma-prone families.”

Of the 293 individuals who enrolled in the study between 1976 and 2014, 246 were diagnosed with melanoma before enrollment (the prestudy cohort) and 47 were diagnosed after enrollment (the prospective cohort). The researchers compared differences in melanoma thickness and tumor stage between participants in the prestudy and prospective cohorts, and compared tumor-thickness trends between participants in their study and cases in the general population using data from Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2016. Because information on melanoma thickness was missing for 24% of melanoma cases in the NCI Familial Melanoma Study and 8.7% of melanoma cases found in the SEER registry, the researchers imputed the missing data.

After adjusting for gender and age, Dr. Sargen and his colleagues found that participants in the prospective cohort had significantly thinner melanomas, compared with those in the prestudy cohort (0.6 mm vs. 1.1 mm, respectively; P < .001). In addition, 83% of those in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage, compared with 40% of those in the prestudy cohort (P < .001).

In their analysis, they also determined that after adjusting for gender and age, “all NCI family cases had systematically lower thickness than SEER cases during the study period.” The reductions in melanoma thickness and tumor stage, they concluded, “were not fully explained by calendar period effects of decreasing thickness in the general population and point to the potential benefit of skin cancer screening for patients with a family history of melanoma and those with pathogenic germline variants of melanoma-susceptibility genes.”

“Our data provide reassuring evidence that screening, alongside education about proper UV protection and the appearance of melanoma, is likely benefiting patients with a significantly elevated risk for melanoma,” Dr. Sargen said in the interview “Further studies are needed to determine whether individuals without a family history of melanoma may benefit from whole-body screening, and whether the benefits vary by ethnicity.”

He acknowledged certain limitations of the study, including the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma-thickness data. “Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention,” he said. “Randomized controlled studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection.”

In an interview, Maryam M. Asgari, MD, professor of dermatology at Harvard University, Boston, called the analysis “well done,” but commented on the potential role of selection bias impacting the findings. “People who have a strong family history of melanoma and who are opting to engage in an NCI study and come in for full-body skin checks and go through that education process may have very different health-seeking behaviors than individuals in the general population that would be reported to SEER,” she said.

She also raised the question of whether the results were driven by the early detection through the NCI’s program of provider screening or through the educational component that enables earlier self-detection. “If you’re an individual involved in a study and that brings attention to your moles and you have a strong family history of melanoma to begin with, it is not surprising that you are going to have heightened awareness of any changing mole and therefore are more likely to have melanoma detected at an earlier stage,” Dr. Asgari said.

The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Sargen reported having no financial disclosures.
Dr. Asgari disclosed that she has received research support from the Melanoma Research Alliance.
 

[email protected]

Patients at very high risk for melanoma, including those with a family history or with inherited pathogenic variants of genes that increase the risk, likely benefit from routine whole-body screening for melanoma and education about UV protection.

Those are key findings from the first prospective cohort study to quantify the benefit of screening in melanoma-prone families, which was published online April 2 in Cancer Epidemiology, Biomarkers & Prevention.

“Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma, which includes people from melanoma-prone families (at least two relatives who have had melanoma) and those with inherited pathogenic gene variants of the CDKN2A or CDK4 genes, which increase risk for melanoma,” lead author Michael R. Sargen, MD, said in an interview. “In our study, we investigated whether screening and educational interventions, including education about the appearance of melanoma and strategies for protecting skin from ultraviolet damage, contributed to early diagnosis of melanoma in individuals from melanoma-prone families.”

Of the 293 individuals who enrolled in the study between 1976 and 2014, 246 were diagnosed with melanoma before enrollment (the prestudy cohort) and 47 were diagnosed after enrollment (the prospective cohort). The researchers compared differences in melanoma thickness and tumor stage between participants in the prestudy and prospective cohorts, and compared tumor-thickness trends between participants in their study and cases in the general population using data from Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2016. Because information on melanoma thickness was missing for 24% of melanoma cases in the NCI Familial Melanoma Study and 8.7% of melanoma cases found in the SEER registry, the researchers imputed the missing data.

After adjusting for gender and age, Dr. Sargen and his colleagues found that participants in the prospective cohort had significantly thinner melanomas, compared with those in the prestudy cohort (0.6 mm vs. 1.1 mm, respectively; P < .001). In addition, 83% of those in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage, compared with 40% of those in the prestudy cohort (P < .001).

In their analysis, they also determined that after adjusting for gender and age, “all NCI family cases had systematically lower thickness than SEER cases during the study period.” The reductions in melanoma thickness and tumor stage, they concluded, “were not fully explained by calendar period effects of decreasing thickness in the general population and point to the potential benefit of skin cancer screening for patients with a family history of melanoma and those with pathogenic germline variants of melanoma-susceptibility genes.”

“Our data provide reassuring evidence that screening, alongside education about proper UV protection and the appearance of melanoma, is likely benefiting patients with a significantly elevated risk for melanoma,” Dr. Sargen said in the interview “Further studies are needed to determine whether individuals without a family history of melanoma may benefit from whole-body screening, and whether the benefits vary by ethnicity.”

He acknowledged certain limitations of the study, including the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma-thickness data. “Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention,” he said. “Randomized controlled studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection.”

In an interview, Maryam M. Asgari, MD, professor of dermatology at Harvard University, Boston, called the analysis “well done,” but commented on the potential role of selection bias impacting the findings. “People who have a strong family history of melanoma and who are opting to engage in an NCI study and come in for full-body skin checks and go through that education process may have very different health-seeking behaviors than individuals in the general population that would be reported to SEER,” she said.

She also raised the question of whether the results were driven by the early detection through the NCI’s program of provider screening or through the educational component that enables earlier self-detection. “If you’re an individual involved in a study and that brings attention to your moles and you have a strong family history of melanoma to begin with, it is not surprising that you are going to have heightened awareness of any changing mole and therefore are more likely to have melanoma detected at an earlier stage,” Dr. Asgari said.

The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Sargen reported having no financial disclosures.
Dr. Asgari disclosed that she has received research support from the Melanoma Research Alliance.
 

[email protected]

Patients at very high risk for melanoma, including those with a family history or with inherited pathogenic variants of genes that increase the risk, likely benefit from routine whole-body screening for melanoma and education about UV protection.

Those are key findings from the first prospective cohort study to quantify the benefit of screening in melanoma-prone families, which was published online April 2 in Cancer Epidemiology, Biomarkers & Prevention.

“Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma, which includes people from melanoma-prone families (at least two relatives who have had melanoma) and those with inherited pathogenic gene variants of the CDKN2A or CDK4 genes, which increase risk for melanoma,” lead author Michael R. Sargen, MD, said in an interview. “In our study, we investigated whether screening and educational interventions, including education about the appearance of melanoma and strategies for protecting skin from ultraviolet damage, contributed to early diagnosis of melanoma in individuals from melanoma-prone families.”

Of the 293 individuals who enrolled in the study between 1976 and 2014, 246 were diagnosed with melanoma before enrollment (the prestudy cohort) and 47 were diagnosed after enrollment (the prospective cohort). The researchers compared differences in melanoma thickness and tumor stage between participants in the prestudy and prospective cohorts, and compared tumor-thickness trends between participants in their study and cases in the general population using data from Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2016. Because information on melanoma thickness was missing for 24% of melanoma cases in the NCI Familial Melanoma Study and 8.7% of melanoma cases found in the SEER registry, the researchers imputed the missing data.

After adjusting for gender and age, Dr. Sargen and his colleagues found that participants in the prospective cohort had significantly thinner melanomas, compared with those in the prestudy cohort (0.6 mm vs. 1.1 mm, respectively; P < .001). In addition, 83% of those in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage, compared with 40% of those in the prestudy cohort (P < .001).

In their analysis, they also determined that after adjusting for gender and age, “all NCI family cases had systematically lower thickness than SEER cases during the study period.” The reductions in melanoma thickness and tumor stage, they concluded, “were not fully explained by calendar period effects of decreasing thickness in the general population and point to the potential benefit of skin cancer screening for patients with a family history of melanoma and those with pathogenic germline variants of melanoma-susceptibility genes.”

“Our data provide reassuring evidence that screening, alongside education about proper UV protection and the appearance of melanoma, is likely benefiting patients with a significantly elevated risk for melanoma,” Dr. Sargen said in the interview “Further studies are needed to determine whether individuals without a family history of melanoma may benefit from whole-body screening, and whether the benefits vary by ethnicity.”

He acknowledged certain limitations of the study, including the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma-thickness data. “Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention,” he said. “Randomized controlled studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection.”

In an interview, Maryam M. Asgari, MD, professor of dermatology at Harvard University, Boston, called the analysis “well done,” but commented on the potential role of selection bias impacting the findings. “People who have a strong family history of melanoma and who are opting to engage in an NCI study and come in for full-body skin checks and go through that education process may have very different health-seeking behaviors than individuals in the general population that would be reported to SEER,” she said.

She also raised the question of whether the results were driven by the early detection through the NCI’s program of provider screening or through the educational component that enables earlier self-detection. “If you’re an individual involved in a study and that brings attention to your moles and you have a strong family history of melanoma to begin with, it is not surprising that you are going to have heightened awareness of any changing mole and therefore are more likely to have melanoma detected at an earlier stage,” Dr. Asgari said.

The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Sargen reported having no financial disclosures.
Dr. Asgari disclosed that she has received research support from the Melanoma Research Alliance.
 

[email protected]

April 5 is the official start date of a U.S. law requiring health care organizations to provide patients with free, full, and immediate electronic access to their doctor’s clinical notes as well as test results and reports from pathology and imaging.

The mandate, called “open notes” by many, is part of the 21st Century Cures Act, a wide-ranging piece of federal health care legislation. The previous deadline of Nov. 2, 2020, for enacting open notes was extended last year because of the exigencies of the COVID-19 pandemic.

Organizations must provide access via patient portals to the following types of notes: consultations, discharge summaries, histories, physical examination findings, imaging narratives, laboratory and pathology report narratives, and procedure and progress notes. Noncompliant organizations will eventually be subject to fines from the Department of Health & Human Services for “information blocking.”

This news organization reported on the mandate in 2020, and some readers said it was an unwelcome intrusion into practice. Since then, this news organization has run additional open notes stories about physician concerns, a perspective essay addressing those fears, and a reader poll about the phenomenon.

Now, as the legislation turns into a practical clinical matter, there are five key points clinicians should consider.
 

Clinicians don’t have to change writing style.

The new law mandates timely patient access to notes and test results, but it doesn’t require that clinicians alter their writing, said Scott MacDonald, MD, an internist and electronic health record medical director at University of California Davis Health in Sacramento.

“You don’t have to change your notes,” he said. However, patients are now part of the note audience and some health care systems are directing clinicians to make patient-friendly style changes.

Everyday experience should guide clinicians when writing notes, said one expert.

“When you’re not sure [of how to write a note], just mirror the way you would speak in the office – that’s going to get you right, including for mental health issues,” advised Leonor Fernandez, MD, an internist at Beth Deaconess Israel Medical Center, Boston, in her “take-away” comments in the online video, How to Write an Open Note.

According to a 2020 Medscape poll of 1,050 physicians, a majority (56%) anticipate that they will write notes differently, knowing that patients can read them via open notes. Nearly two-thirds (64%) believe that this new wrinkle in medical records will increase their workload. However, actual practice suggests that this is true for a minority of practitioners, according to the results from a recent study of more than 1,000 physicians in Boston, Seattle, and rural Pennsylvania, who already work in open notes settings. Only about one-third (37%) reported “spending more time on documentation.”

Note writing is going to change because of the addition of the patient reader, and something will be lost, argued Steven Reidbord, MD, a psychiatrist in private practice in San Francisco. By watering down the language for patients, “you are trading away the technical precision and other advantages of having a professional language,” commented Dr. Reidbord, who blogs for Psychology Today and has criticized the open notes movement in the past.

However, years of investigation from OpenNotes, the Boston-based advocacy and research organization, indicates that there are many gains with patient-accessible notes, including improved medical record accuracy, greater medication adherence, and potentially improved health care disparities among a range of patient types. In a 2019 study, researchers said that worry and confusion among note-reading patients are uncommon (5% and 3%, respectively), which addresses two criticisms voiced by multiple people last year.
 

Some clinical notes can be withheld. 

The new rules from the federal government permit information blocking if there is clear evidence that doing so “will substantially reduce the risk of harm” to patients or to other third parties, Tom Delbanco, MD, and Charlotte Blease, PhD, of OpenNotes in Boston wrote in a commentary in February 2021.

There are also state-level laws that can supersede the new U.S. law and block access to notes, points out MacDonald. For example, California law dictates that providers cannot post cancer test results without talking with the patient first.

The OpenNotes organization also points out that, with regard to sensitive psychotherapy notes that are separated from the rest of a medical record, those notes “can be kept from patients without their permission, and such rules vary state by state.”
 

Some patients are more likely readers. 

Some patients are more likely to peer into their files than others, said Liz Salmi, senior strategist at OpenNotes, who is also a brain cancer patient.

“Those patients who have more serious or chronic conditions ... are more likely to read their notes,” she said in an interview.

A new study of nearly 6,000 medical oncology patients at the University of Wisconsin confirmed that opinion. Patients with incurable metastatic disease were much more likely than those with early-stage, curable disease to read notes. Notably, younger patients were more likely than older ones to access notes, likely the result of generational tech savvy.

Despite the unpredictability of serious disease such as cancer, oncology patients find satisfaction in reading their notes, say experts. “We’ve overwhelmingly heard that patients like it,” Thomas LeBlanc, MD, medical oncologist at Duke University, Durham, N.C., where all patients already have access to clinicians’ notes, told this news organization in 2018.
 

You are part of the avant garde. 

The United States and Scandinavian countries are the world leaders in implementing open notes in clinical practice, Dr. Blease said in an interview.

“It’s a phenomenal achievement” to have enacted open notes nationally, she said. For example, there are no open notes in Northern Ireland, Dr. Blease’s home country, or most of Europe.

In the United States, there are more than 200 medical organizations, including at least one in every state, that were voluntarily providing open notes before April 5, including interstate giants such as Banner Health and big-name medical centers such as Cleveland Clinic.

It may be hard for the United States to top Sweden’s embrace of the practice. The national open notes program now has 7.2 million patient accounts in a country of 10 million people, noted Maria Häggland, PhD, of Uppsala (Sweden) MedTech Science Innovation Center during a webinar last year.
 

The start day will come, and you may not notice. 

“When April 5 happens, something brand new is going to happen symbolically,” Ms. Salmi said. Its importance is hard to measure.

“Patients say they trust their doctor more because they understand their thinking with open notes. How do you value that? We don’t have metrics for that,” she said.

Dr. MacDonald suggested that open notes are both new and not new. In the fall of 2020, he predicted that the launch day would come, and few clinicians would notice, in part because many patients already access truncated information via patient portals.

However, there are “sensitive issues,” such as with adolescents and reproductive health, where “we know that some parents have sign-in information for their teen’s portal,” he commented. With clinical notes now on full display, potential problems “may be out of our control.”

Still, the Sacramento-based physician and IT officer acknowledged that concerns about open notes may be a bit inflated. “I’ve been more worried about reassuring physicians that everything will be okay than what’s actually going to happen [as the law takes effect],” Dr. MacDonald said.

The OpenNotes organization is grant funded, and staff disclosed no relevant financial relationships.

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

April 5 is the official start date of a U.S. law requiring health care organizations to provide patients with free, full, and immediate electronic access to their doctor’s clinical notes as well as test results and reports from pathology and imaging.

The mandate, called “open notes” by many, is part of the 21st Century Cures Act, a wide-ranging piece of federal health care legislation. The previous deadline of Nov. 2, 2020, for enacting open notes was extended last year because of the exigencies of the COVID-19 pandemic.

Organizations must provide access via patient portals to the following types of notes: consultations, discharge summaries, histories, physical examination findings, imaging narratives, laboratory and pathology report narratives, and procedure and progress notes. Noncompliant organizations will eventually be subject to fines from the Department of Health & Human Services for “information blocking.”

This news organization reported on the mandate in 2020, and some readers said it was an unwelcome intrusion into practice. Since then, this news organization has run additional open notes stories about physician concerns, a perspective essay addressing those fears, and a reader poll about the phenomenon.

Now, as the legislation turns into a practical clinical matter, there are five key points clinicians should consider.
 

Clinicians don’t have to change writing style.

The new law mandates timely patient access to notes and test results, but it doesn’t require that clinicians alter their writing, said Scott MacDonald, MD, an internist and electronic health record medical director at University of California Davis Health in Sacramento.

“You don’t have to change your notes,” he said. However, patients are now part of the note audience and some health care systems are directing clinicians to make patient-friendly style changes.

Everyday experience should guide clinicians when writing notes, said one expert.

“When you’re not sure [of how to write a note], just mirror the way you would speak in the office – that’s going to get you right, including for mental health issues,” advised Leonor Fernandez, MD, an internist at Beth Deaconess Israel Medical Center, Boston, in her “take-away” comments in the online video, How to Write an Open Note.

According to a 2020 Medscape poll of 1,050 physicians, a majority (56%) anticipate that they will write notes differently, knowing that patients can read them via open notes. Nearly two-thirds (64%) believe that this new wrinkle in medical records will increase their workload. However, actual practice suggests that this is true for a minority of practitioners, according to the results from a recent study of more than 1,000 physicians in Boston, Seattle, and rural Pennsylvania, who already work in open notes settings. Only about one-third (37%) reported “spending more time on documentation.”

Note writing is going to change because of the addition of the patient reader, and something will be lost, argued Steven Reidbord, MD, a psychiatrist in private practice in San Francisco. By watering down the language for patients, “you are trading away the technical precision and other advantages of having a professional language,” commented Dr. Reidbord, who blogs for Psychology Today and has criticized the open notes movement in the past.

However, years of investigation from OpenNotes, the Boston-based advocacy and research organization, indicates that there are many gains with patient-accessible notes, including improved medical record accuracy, greater medication adherence, and potentially improved health care disparities among a range of patient types. In a 2019 study, researchers said that worry and confusion among note-reading patients are uncommon (5% and 3%, respectively), which addresses two criticisms voiced by multiple people last year.
 

Some clinical notes can be withheld. 

The new rules from the federal government permit information blocking if there is clear evidence that doing so “will substantially reduce the risk of harm” to patients or to other third parties, Tom Delbanco, MD, and Charlotte Blease, PhD, of OpenNotes in Boston wrote in a commentary in February 2021.

There are also state-level laws that can supersede the new U.S. law and block access to notes, points out MacDonald. For example, California law dictates that providers cannot post cancer test results without talking with the patient first.

The OpenNotes organization also points out that, with regard to sensitive psychotherapy notes that are separated from the rest of a medical record, those notes “can be kept from patients without their permission, and such rules vary state by state.”
 

Some patients are more likely readers. 

Some patients are more likely to peer into their files than others, said Liz Salmi, senior strategist at OpenNotes, who is also a brain cancer patient.

“Those patients who have more serious or chronic conditions ... are more likely to read their notes,” she said in an interview.

A new study of nearly 6,000 medical oncology patients at the University of Wisconsin confirmed that opinion. Patients with incurable metastatic disease were much more likely than those with early-stage, curable disease to read notes. Notably, younger patients were more likely than older ones to access notes, likely the result of generational tech savvy.

Despite the unpredictability of serious disease such as cancer, oncology patients find satisfaction in reading their notes, say experts. “We’ve overwhelmingly heard that patients like it,” Thomas LeBlanc, MD, medical oncologist at Duke University, Durham, N.C., where all patients already have access to clinicians’ notes, told this news organization in 2018.
 

You are part of the avant garde. 

The United States and Scandinavian countries are the world leaders in implementing open notes in clinical practice, Dr. Blease said in an interview.

“It’s a phenomenal achievement” to have enacted open notes nationally, she said. For example, there are no open notes in Northern Ireland, Dr. Blease’s home country, or most of Europe.

In the United States, there are more than 200 medical organizations, including at least one in every state, that were voluntarily providing open notes before April 5, including interstate giants such as Banner Health and big-name medical centers such as Cleveland Clinic.

It may be hard for the United States to top Sweden’s embrace of the practice. The national open notes program now has 7.2 million patient accounts in a country of 10 million people, noted Maria Häggland, PhD, of Uppsala (Sweden) MedTech Science Innovation Center during a webinar last year.
 

The start day will come, and you may not notice. 

“When April 5 happens, something brand new is going to happen symbolically,” Ms. Salmi said. Its importance is hard to measure.

“Patients say they trust their doctor more because they understand their thinking with open notes. How do you value that? We don’t have metrics for that,” she said.

Dr. MacDonald suggested that open notes are both new and not new. In the fall of 2020, he predicted that the launch day would come, and few clinicians would notice, in part because many patients already access truncated information via patient portals.

However, there are “sensitive issues,” such as with adolescents and reproductive health, where “we know that some parents have sign-in information for their teen’s portal,” he commented. With clinical notes now on full display, potential problems “may be out of our control.”

Still, the Sacramento-based physician and IT officer acknowledged that concerns about open notes may be a bit inflated. “I’ve been more worried about reassuring physicians that everything will be okay than what’s actually going to happen [as the law takes effect],” Dr. MacDonald said.

The OpenNotes organization is grant funded, and staff disclosed no relevant financial relationships.

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

April 5 is the official start date of a U.S. law requiring health care organizations to provide patients with free, full, and immediate electronic access to their doctor’s clinical notes as well as test results and reports from pathology and imaging.

The mandate, called “open notes” by many, is part of the 21st Century Cures Act, a wide-ranging piece of federal health care legislation. The previous deadline of Nov. 2, 2020, for enacting open notes was extended last year because of the exigencies of the COVID-19 pandemic.

Organizations must provide access via patient portals to the following types of notes: consultations, discharge summaries, histories, physical examination findings, imaging narratives, laboratory and pathology report narratives, and procedure and progress notes. Noncompliant organizations will eventually be subject to fines from the Department of Health & Human Services for “information blocking.”

This news organization reported on the mandate in 2020, and some readers said it was an unwelcome intrusion into practice. Since then, this news organization has run additional open notes stories about physician concerns, a perspective essay addressing those fears, and a reader poll about the phenomenon.

Now, as the legislation turns into a practical clinical matter, there are five key points clinicians should consider.
 

Clinicians don’t have to change writing style.

The new law mandates timely patient access to notes and test results, but it doesn’t require that clinicians alter their writing, said Scott MacDonald, MD, an internist and electronic health record medical director at University of California Davis Health in Sacramento.

“You don’t have to change your notes,” he said. However, patients are now part of the note audience and some health care systems are directing clinicians to make patient-friendly style changes.

Everyday experience should guide clinicians when writing notes, said one expert.

“When you’re not sure [of how to write a note], just mirror the way you would speak in the office – that’s going to get you right, including for mental health issues,” advised Leonor Fernandez, MD, an internist at Beth Deaconess Israel Medical Center, Boston, in her “take-away” comments in the online video, How to Write an Open Note.

According to a 2020 Medscape poll of 1,050 physicians, a majority (56%) anticipate that they will write notes differently, knowing that patients can read them via open notes. Nearly two-thirds (64%) believe that this new wrinkle in medical records will increase their workload. However, actual practice suggests that this is true for a minority of practitioners, according to the results from a recent study of more than 1,000 physicians in Boston, Seattle, and rural Pennsylvania, who already work in open notes settings. Only about one-third (37%) reported “spending more time on documentation.”

Note writing is going to change because of the addition of the patient reader, and something will be lost, argued Steven Reidbord, MD, a psychiatrist in private practice in San Francisco. By watering down the language for patients, “you are trading away the technical precision and other advantages of having a professional language,” commented Dr. Reidbord, who blogs for Psychology Today and has criticized the open notes movement in the past.

However, years of investigation from OpenNotes, the Boston-based advocacy and research organization, indicates that there are many gains with patient-accessible notes, including improved medical record accuracy, greater medication adherence, and potentially improved health care disparities among a range of patient types. In a 2019 study, researchers said that worry and confusion among note-reading patients are uncommon (5% and 3%, respectively), which addresses two criticisms voiced by multiple people last year.
 

Some clinical notes can be withheld. 

The new rules from the federal government permit information blocking if there is clear evidence that doing so “will substantially reduce the risk of harm” to patients or to other third parties, Tom Delbanco, MD, and Charlotte Blease, PhD, of OpenNotes in Boston wrote in a commentary in February 2021.

There are also state-level laws that can supersede the new U.S. law and block access to notes, points out MacDonald. For example, California law dictates that providers cannot post cancer test results without talking with the patient first.

The OpenNotes organization also points out that, with regard to sensitive psychotherapy notes that are separated from the rest of a medical record, those notes “can be kept from patients without their permission, and such rules vary state by state.”
 

Some patients are more likely readers. 

Some patients are more likely to peer into their files than others, said Liz Salmi, senior strategist at OpenNotes, who is also a brain cancer patient.

“Those patients who have more serious or chronic conditions ... are more likely to read their notes,” she said in an interview.

A new study of nearly 6,000 medical oncology patients at the University of Wisconsin confirmed that opinion. Patients with incurable metastatic disease were much more likely than those with early-stage, curable disease to read notes. Notably, younger patients were more likely than older ones to access notes, likely the result of generational tech savvy.

Despite the unpredictability of serious disease such as cancer, oncology patients find satisfaction in reading their notes, say experts. “We’ve overwhelmingly heard that patients like it,” Thomas LeBlanc, MD, medical oncologist at Duke University, Durham, N.C., where all patients already have access to clinicians’ notes, told this news organization in 2018.
 

You are part of the avant garde. 

The United States and Scandinavian countries are the world leaders in implementing open notes in clinical practice, Dr. Blease said in an interview.

“It’s a phenomenal achievement” to have enacted open notes nationally, she said. For example, there are no open notes in Northern Ireland, Dr. Blease’s home country, or most of Europe.

In the United States, there are more than 200 medical organizations, including at least one in every state, that were voluntarily providing open notes before April 5, including interstate giants such as Banner Health and big-name medical centers such as Cleveland Clinic.

It may be hard for the United States to top Sweden’s embrace of the practice. The national open notes program now has 7.2 million patient accounts in a country of 10 million people, noted Maria Häggland, PhD, of Uppsala (Sweden) MedTech Science Innovation Center during a webinar last year.
 

The start day will come, and you may not notice. 

“When April 5 happens, something brand new is going to happen symbolically,” Ms. Salmi said. Its importance is hard to measure.

“Patients say they trust their doctor more because they understand their thinking with open notes. How do you value that? We don’t have metrics for that,” she said.

Dr. MacDonald suggested that open notes are both new and not new. In the fall of 2020, he predicted that the launch day would come, and few clinicians would notice, in part because many patients already access truncated information via patient portals.

However, there are “sensitive issues,” such as with adolescents and reproductive health, where “we know that some parents have sign-in information for their teen’s portal,” he commented. With clinical notes now on full display, potential problems “may be out of our control.”

Still, the Sacramento-based physician and IT officer acknowledged that concerns about open notes may be a bit inflated. “I’ve been more worried about reassuring physicians that everything will be okay than what’s actually going to happen [as the law takes effect],” Dr. MacDonald said.

The OpenNotes organization is grant funded, and staff disclosed no relevant financial relationships.

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

Significant survival gains were seen when the immune checkpoint inhibitor camrelizumab was added to standard chemotherapy for the first-line treatment of advanced squamous non–small cell lung cancer (NSCLC) in a phase 3 trial conducted in China.

Results of the CAMEL-sq trial showed a progression-free survival (PFS) advantage of 3.6 months with camrelizumab plus chemotherapy, compared with chemotherapy plus placebo (P < .0001). The median overall survival (OS) was not reached in the camrelizumab arm, but it was significantly better than in the placebo arm (P < .0001).

Camrelizumab plus chemotherapy is already a standard of care in China for patients with advanced nonsquamous NSCLC who are negative for EGFR and ALK mutations, study investigator Caicun Zhou, MD, PhD, said when presenting the CAMEL-sq results at the European Lung Cancer Virtual Congress 2021 (Abstract 96O).

The CAMEL-sq findings now support the combination as a “standard first-line treatment for advanced squamous NSCLC,” said Dr. Zhou of Shanghai Pulmonary Hospital and Tongji University.

“The study has kind of changed our daily practice,” he said. “I do think we will have the label, camrelizumab plus chemo as first-line treatment for squamous [NSCLC] in China, maybe in a couple of months.”

“Camrelizumab will most likely be another brick in the wall for our Chinese patients and colleagues to use for patients with squamous histology, non–small cell lung cancer in addition to pembrolizumab,” said Julie Renee Brahmer, MD, of Johns Hopkins Medicine in Baltimore, who was the invited discussant for the trial.

Dr. Brahmer noted that the PFS hazard ratio in this trial – 0.37 – was “impressive.”
 

Patients and treatment

CAMEL-sq is a phase 3, double-blind, multicenter trial. The 390 patients enrolled had pathologically-confirmed stage IIIB or IV squamous NSCLC, and they had not received any prior treatment.

Patients received four to six cycles of chemotherapy, consisting of carboplatin and paclitaxel given every 3 weeks. Camrelizumab was added to one arm at a dose of 200 mg, and placebo was added to the other.

This was followed by a maintenance phase in which patients remained on active treatment with camrelizumab or placebo for up to 2 years. Patients in the placebo arm could cross over to camrelizumab at progression.

The median age of patients was similar in the camrelizumab and placebo arms (64 years and 62 years, respectively). The majority of study subjects in both arms were men (more than 90%), had a history of smoking (more than 80%), and had stage IV disease (more than 70%).
 

Efficacy and safety

The median PFS was 8.5 months in the camrelizumab arm and 4.9 months in the placebo arm (HR, 0.37; P < .0001). The median OS was not reached in the camrelizumab arm and was 14.5 months in the placebo arm (HR, 0.55, P < .0001).

The survival benefits were observed in spite of a crossover rate of 46.9%, Dr. Zhou noted.

Furthermore, survival benefits were consistent across all the subgroups tested. Regardless of age, sex, performance status, smoking history, disease stage, presence of liver or brain metastases, or PD-L1 expression, there was an apparent advantage of camrelizumab over placebo.

The objective response rate was higher in the camrelizumab arm than in the placebo arm, at 64.8% and 36.7%, respectively (P < .0001).

The clinical response seen with camrelizumab was “robust and durable,” Dr. Zhou said. Indeed, the duration of response was 13.1 months in the camrelizumab arm and 4.4 months in the placebo arm.

Grade 3/4 treatment-related adverse events (AEs) were reported in a similar percentage of camrelizumab- or placebo-treated patients (73.6% and 71.4%, respectively). However, “the majority of treatment-related adverse effects were chemotherapy related,” Dr. Zhou pointed out. This included decreased total white blood cell, neutrophil, red blood cell, and platelet counts as well as alopecia and increased liver enzymes.

Immune-related AEs occurred in 76.7% of patients in the camrelizumab arm and 20.4% of those in the placebo arm.

“The majority of immune-related adverse events were grade 1 or grade 2; easily manageable in our daily practice,” Dr. Zhou noted.
 

Putting CAMEL-sq into perspective

Data from other trials of immunotherapy-chemotherapy combinations in squamous NSCLC have been presented recently but with less impressive results, Dr. Brahmer said.

In one trial – ORIENT-12 – sintilimab was combined with gemcitabine and cisplatin (ESMO 2020, Abstract LBA56). The median PFS, per investigators, was 5.5 months with sintilimab and 4.9 months without it, both of which are lower than the 8.5 months seen with camrelizumab plus chemotherapy in the CAMEL-sq trial.

Another trial is KEYNOTE-407, in which patients received pembrolizumab or placebo plus a carboplatin-paclitaxel (or nab-paclitaxel) regimen. Three-year follow-up data from the trial were presented at ELCC 2021 (Abstract 97O). Continued improvements in second PFS (HR, 0.59) and OS (HR, 0.71) were observed with pembrolizumab-chemotherapy versus placebo-chemotherapy.

“We have to remember the high PD-L1-negative disease rate in the CAMEL-sq study, compared to the KEYNOTE-407 rate,” before stacking the two studies against each other, Dr. Brahmer noted. In KEYNOTE-407, almost 35% of patients had PD-L1 expression of less than 1%, compared with nearly 50% in the CAMEL-sq study.

That aside, “very similar impressive 1-year progression-free survival rates are seen on both studies,” Dr. Brahmer said. “I hope that camrelizumab has continued follow-up so we can see how these patients will do long-term.

“My eyebrows were raised a little bit at the camrelizumab immune-related AE rate of almost 76%, compared to the immune-related AE rate of about 36% in the KEYNOTE-407 study,” Dr. Brahmer said.

She noted, however, that almost two-thirds of the immune-related AEs in CAMEL-sq were due to reactive cutaneous capillary endothelial proliferation, which doesn’t appear to have been previously reported with PD-1 or PD-L1 inhibitors. This is a side effect seen in studies of liver cancer and may be linked to PFS, Dr. Brahmer said.

CAMEL-sq is funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Zhou disclosed honoraria from multiple pharmaceutical companies, including the study sponsor. Two of Dr. Zhou’s coauthors are employees of the company. Dr. Brahmer disclosed relationships with Amgen, Bristol Myers Squibb, Eli Lily, GlaxoSmithKline, Merck, Sanofi, Easi, AstraZeneca, Genentech, Regeneron, and RAPT Therapeutics Inc.

Significant survival gains were seen when the immune checkpoint inhibitor camrelizumab was added to standard chemotherapy for the first-line treatment of advanced squamous non–small cell lung cancer (NSCLC) in a phase 3 trial conducted in China.

Results of the CAMEL-sq trial showed a progression-free survival (PFS) advantage of 3.6 months with camrelizumab plus chemotherapy, compared with chemotherapy plus placebo (P < .0001). The median overall survival (OS) was not reached in the camrelizumab arm, but it was significantly better than in the placebo arm (P < .0001).

Camrelizumab plus chemotherapy is already a standard of care in China for patients with advanced nonsquamous NSCLC who are negative for EGFR and ALK mutations, study investigator Caicun Zhou, MD, PhD, said when presenting the CAMEL-sq results at the European Lung Cancer Virtual Congress 2021 (Abstract 96O).

The CAMEL-sq findings now support the combination as a “standard first-line treatment for advanced squamous NSCLC,” said Dr. Zhou of Shanghai Pulmonary Hospital and Tongji University.

“The study has kind of changed our daily practice,” he said. “I do think we will have the label, camrelizumab plus chemo as first-line treatment for squamous [NSCLC] in China, maybe in a couple of months.”

“Camrelizumab will most likely be another brick in the wall for our Chinese patients and colleagues to use for patients with squamous histology, non–small cell lung cancer in addition to pembrolizumab,” said Julie Renee Brahmer, MD, of Johns Hopkins Medicine in Baltimore, who was the invited discussant for the trial.

Dr. Brahmer noted that the PFS hazard ratio in this trial – 0.37 – was “impressive.”
 

Patients and treatment

CAMEL-sq is a phase 3, double-blind, multicenter trial. The 390 patients enrolled had pathologically-confirmed stage IIIB or IV squamous NSCLC, and they had not received any prior treatment.

Patients received four to six cycles of chemotherapy, consisting of carboplatin and paclitaxel given every 3 weeks. Camrelizumab was added to one arm at a dose of 200 mg, and placebo was added to the other.

This was followed by a maintenance phase in which patients remained on active treatment with camrelizumab or placebo for up to 2 years. Patients in the placebo arm could cross over to camrelizumab at progression.

The median age of patients was similar in the camrelizumab and placebo arms (64 years and 62 years, respectively). The majority of study subjects in both arms were men (more than 90%), had a history of smoking (more than 80%), and had stage IV disease (more than 70%).
 

Efficacy and safety

The median PFS was 8.5 months in the camrelizumab arm and 4.9 months in the placebo arm (HR, 0.37; P < .0001). The median OS was not reached in the camrelizumab arm and was 14.5 months in the placebo arm (HR, 0.55, P < .0001).

The survival benefits were observed in spite of a crossover rate of 46.9%, Dr. Zhou noted.

Furthermore, survival benefits were consistent across all the subgroups tested. Regardless of age, sex, performance status, smoking history, disease stage, presence of liver or brain metastases, or PD-L1 expression, there was an apparent advantage of camrelizumab over placebo.

The objective response rate was higher in the camrelizumab arm than in the placebo arm, at 64.8% and 36.7%, respectively (P < .0001).

The clinical response seen with camrelizumab was “robust and durable,” Dr. Zhou said. Indeed, the duration of response was 13.1 months in the camrelizumab arm and 4.4 months in the placebo arm.

Grade 3/4 treatment-related adverse events (AEs) were reported in a similar percentage of camrelizumab- or placebo-treated patients (73.6% and 71.4%, respectively). However, “the majority of treatment-related adverse effects were chemotherapy related,” Dr. Zhou pointed out. This included decreased total white blood cell, neutrophil, red blood cell, and platelet counts as well as alopecia and increased liver enzymes.

Immune-related AEs occurred in 76.7% of patients in the camrelizumab arm and 20.4% of those in the placebo arm.

“The majority of immune-related adverse events were grade 1 or grade 2; easily manageable in our daily practice,” Dr. Zhou noted.
 

Putting CAMEL-sq into perspective

Data from other trials of immunotherapy-chemotherapy combinations in squamous NSCLC have been presented recently but with less impressive results, Dr. Brahmer said.

In one trial – ORIENT-12 – sintilimab was combined with gemcitabine and cisplatin (ESMO 2020, Abstract LBA56). The median PFS, per investigators, was 5.5 months with sintilimab and 4.9 months without it, both of which are lower than the 8.5 months seen with camrelizumab plus chemotherapy in the CAMEL-sq trial.

Another trial is KEYNOTE-407, in which patients received pembrolizumab or placebo plus a carboplatin-paclitaxel (or nab-paclitaxel) regimen. Three-year follow-up data from the trial were presented at ELCC 2021 (Abstract 97O). Continued improvements in second PFS (HR, 0.59) and OS (HR, 0.71) were observed with pembrolizumab-chemotherapy versus placebo-chemotherapy.

“We have to remember the high PD-L1-negative disease rate in the CAMEL-sq study, compared to the KEYNOTE-407 rate,” before stacking the two studies against each other, Dr. Brahmer noted. In KEYNOTE-407, almost 35% of patients had PD-L1 expression of less than 1%, compared with nearly 50% in the CAMEL-sq study.

That aside, “very similar impressive 1-year progression-free survival rates are seen on both studies,” Dr. Brahmer said. “I hope that camrelizumab has continued follow-up so we can see how these patients will do long-term.

“My eyebrows were raised a little bit at the camrelizumab immune-related AE rate of almost 76%, compared to the immune-related AE rate of about 36% in the KEYNOTE-407 study,” Dr. Brahmer said.

She noted, however, that almost two-thirds of the immune-related AEs in CAMEL-sq were due to reactive cutaneous capillary endothelial proliferation, which doesn’t appear to have been previously reported with PD-1 or PD-L1 inhibitors. This is a side effect seen in studies of liver cancer and may be linked to PFS, Dr. Brahmer said.

CAMEL-sq is funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Zhou disclosed honoraria from multiple pharmaceutical companies, including the study sponsor. Two of Dr. Zhou’s coauthors are employees of the company. Dr. Brahmer disclosed relationships with Amgen, Bristol Myers Squibb, Eli Lily, GlaxoSmithKline, Merck, Sanofi, Easi, AstraZeneca, Genentech, Regeneron, and RAPT Therapeutics Inc.

Significant survival gains were seen when the immune checkpoint inhibitor camrelizumab was added to standard chemotherapy for the first-line treatment of advanced squamous non–small cell lung cancer (NSCLC) in a phase 3 trial conducted in China.

Results of the CAMEL-sq trial showed a progression-free survival (PFS) advantage of 3.6 months with camrelizumab plus chemotherapy, compared with chemotherapy plus placebo (P < .0001). The median overall survival (OS) was not reached in the camrelizumab arm, but it was significantly better than in the placebo arm (P < .0001).

Camrelizumab plus chemotherapy is already a standard of care in China for patients with advanced nonsquamous NSCLC who are negative for EGFR and ALK mutations, study investigator Caicun Zhou, MD, PhD, said when presenting the CAMEL-sq results at the European Lung Cancer Virtual Congress 2021 (Abstract 96O).

The CAMEL-sq findings now support the combination as a “standard first-line treatment for advanced squamous NSCLC,” said Dr. Zhou of Shanghai Pulmonary Hospital and Tongji University.

“The study has kind of changed our daily practice,” he said. “I do think we will have the label, camrelizumab plus chemo as first-line treatment for squamous [NSCLC] in China, maybe in a couple of months.”

“Camrelizumab will most likely be another brick in the wall for our Chinese patients and colleagues to use for patients with squamous histology, non–small cell lung cancer in addition to pembrolizumab,” said Julie Renee Brahmer, MD, of Johns Hopkins Medicine in Baltimore, who was the invited discussant for the trial.

Dr. Brahmer noted that the PFS hazard ratio in this trial – 0.37 – was “impressive.”
 

Patients and treatment

CAMEL-sq is a phase 3, double-blind, multicenter trial. The 390 patients enrolled had pathologically-confirmed stage IIIB or IV squamous NSCLC, and they had not received any prior treatment.

Patients received four to six cycles of chemotherapy, consisting of carboplatin and paclitaxel given every 3 weeks. Camrelizumab was added to one arm at a dose of 200 mg, and placebo was added to the other.

This was followed by a maintenance phase in which patients remained on active treatment with camrelizumab or placebo for up to 2 years. Patients in the placebo arm could cross over to camrelizumab at progression.

The median age of patients was similar in the camrelizumab and placebo arms (64 years and 62 years, respectively). The majority of study subjects in both arms were men (more than 90%), had a history of smoking (more than 80%), and had stage IV disease (more than 70%).
 

Efficacy and safety

The median PFS was 8.5 months in the camrelizumab arm and 4.9 months in the placebo arm (HR, 0.37; P < .0001). The median OS was not reached in the camrelizumab arm and was 14.5 months in the placebo arm (HR, 0.55, P < .0001).

The survival benefits were observed in spite of a crossover rate of 46.9%, Dr. Zhou noted.

Furthermore, survival benefits were consistent across all the subgroups tested. Regardless of age, sex, performance status, smoking history, disease stage, presence of liver or brain metastases, or PD-L1 expression, there was an apparent advantage of camrelizumab over placebo.

The objective response rate was higher in the camrelizumab arm than in the placebo arm, at 64.8% and 36.7%, respectively (P < .0001).

The clinical response seen with camrelizumab was “robust and durable,” Dr. Zhou said. Indeed, the duration of response was 13.1 months in the camrelizumab arm and 4.4 months in the placebo arm.

Grade 3/4 treatment-related adverse events (AEs) were reported in a similar percentage of camrelizumab- or placebo-treated patients (73.6% and 71.4%, respectively). However, “the majority of treatment-related adverse effects were chemotherapy related,” Dr. Zhou pointed out. This included decreased total white blood cell, neutrophil, red blood cell, and platelet counts as well as alopecia and increased liver enzymes.

Immune-related AEs occurred in 76.7% of patients in the camrelizumab arm and 20.4% of those in the placebo arm.

“The majority of immune-related adverse events were grade 1 or grade 2; easily manageable in our daily practice,” Dr. Zhou noted.
 

Putting CAMEL-sq into perspective

Data from other trials of immunotherapy-chemotherapy combinations in squamous NSCLC have been presented recently but with less impressive results, Dr. Brahmer said.

In one trial – ORIENT-12 – sintilimab was combined with gemcitabine and cisplatin (ESMO 2020, Abstract LBA56). The median PFS, per investigators, was 5.5 months with sintilimab and 4.9 months without it, both of which are lower than the 8.5 months seen with camrelizumab plus chemotherapy in the CAMEL-sq trial.

Another trial is KEYNOTE-407, in which patients received pembrolizumab or placebo plus a carboplatin-paclitaxel (or nab-paclitaxel) regimen. Three-year follow-up data from the trial were presented at ELCC 2021 (Abstract 97O). Continued improvements in second PFS (HR, 0.59) and OS (HR, 0.71) were observed with pembrolizumab-chemotherapy versus placebo-chemotherapy.

“We have to remember the high PD-L1-negative disease rate in the CAMEL-sq study, compared to the KEYNOTE-407 rate,” before stacking the two studies against each other, Dr. Brahmer noted. In KEYNOTE-407, almost 35% of patients had PD-L1 expression of less than 1%, compared with nearly 50% in the CAMEL-sq study.

That aside, “very similar impressive 1-year progression-free survival rates are seen on both studies,” Dr. Brahmer said. “I hope that camrelizumab has continued follow-up so we can see how these patients will do long-term.

“My eyebrows were raised a little bit at the camrelizumab immune-related AE rate of almost 76%, compared to the immune-related AE rate of about 36% in the KEYNOTE-407 study,” Dr. Brahmer said.

She noted, however, that almost two-thirds of the immune-related AEs in CAMEL-sq were due to reactive cutaneous capillary endothelial proliferation, which doesn’t appear to have been previously reported with PD-1 or PD-L1 inhibitors. This is a side effect seen in studies of liver cancer and may be linked to PFS, Dr. Brahmer said.

CAMEL-sq is funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Zhou disclosed honoraria from multiple pharmaceutical companies, including the study sponsor. Two of Dr. Zhou’s coauthors are employees of the company. Dr. Brahmer disclosed relationships with Amgen, Bristol Myers Squibb, Eli Lily, GlaxoSmithKline, Merck, Sanofi, Easi, AstraZeneca, Genentech, Regeneron, and RAPT Therapeutics Inc.

Judicious organ matching for older liver transplant candidates with hepatocellular carcinoma (HCC) leads to survival outcomes similar to those in younger recipients, a case review suggests.

Overall survival (OS) rates among transplant recipients included in a prospective institutional database were 85.5% and 84% at 3 years after liver transplant in patients aged 65 years and under and those over 65 years, respectively. The 5-year survival rates were 73.9% and 77%, respectively (P = .26), Ola Ahmed, MD, of the department of abdominal organ transplantation surgery at Washington University, St. Louis, and colleagues found.

The investigators looked at 1,629 patients diagnosed with HCC between Jan. 1, 2002, and Dec. 31, 2019 of whom 700 were considered for curative surgery, including transplant in 538, and resection in 162.

The patients had a mean age of 62.8 years. Those older than 65 years were less likely to be considered or listed for transplant (27% vs. 73%, P < .01), although oncologic staging and delisting rates were similar in both groups. “This observation still holds true after controlling for other variables, including viral hepatitis and gender in the multivariable analysis (adjusted odds ratio, 0.365),” the investigators reported in the Journal of the American College of Surgeons.

The findings were also reported at the 2020 virtual Western Surgical Association 128th Scientific Session in November.
 

The issue of resection

Surgical intervention occurred in 597 patients, including 392 and 205 aged 65 years and younger and over 65 years, respectively.

OS was lower among patients who underwent resection, compared with the liver transplant recipients, but was similar in the older and younger age groups (3-year OS, 59% vs. 64.8% and 5-year OS, 44.8% vs. 49%; P = .13). No differences were noted in the development of local or distant metastatic disease after transplant or resection.

The two age groups had comparable ICU stays (2 days) and total hospital length of stay (6 days). There were no differences in 30- and 90-day hospital readmissions, they noted.

“On additional age analysis, 65% of transplanted patients over 65 years are currently alive and were disease free at the end of the study period, compared to only 18% of their resected counterparts (P < .01),” they wrote.

Justifying transplant

The findings are notable because despite the effectiveness of transplant as an alternative treatment for unresectable HCC, older patients are often excluded from consideration for transplant. Most studies over the past 15 years have focused on patients aged under 60 years and the ability to extrapolate results to older patients has been limited. Further, results have been conflicting in older patients, the authors explained.

“This is particularly apposite at this time with prolonged life expectancy and the growing interest in improving cancer survivorship,” they noted, adding that “there is logic in challenging existing gold standards and traditional norms with real-life medical practice.

Indeed, the current findings suggest – perhaps contrary to common perceptions – that transplant in carefully selected patients “can be justified in older age groups and provide clinically meaningful and longer survival benefits,” they said, adding that “discussions should be guided by the potential for unfair age discriminations and precise terminology of physiologic rather than actual age.

“Such insights highlight the continued need for quality improvement in the surgical management of older patients, raising questions regarding current resource utilization among different age groups and how age can influence patterns of cancer care,” they concluded.

The authors reported having no disclosures.

[email protected]

Judicious organ matching for older liver transplant candidates with hepatocellular carcinoma (HCC) leads to survival outcomes similar to those in younger recipients, a case review suggests.

Overall survival (OS) rates among transplant recipients included in a prospective institutional database were 85.5% and 84% at 3 years after liver transplant in patients aged 65 years and under and those over 65 years, respectively. The 5-year survival rates were 73.9% and 77%, respectively (P = .26), Ola Ahmed, MD, of the department of abdominal organ transplantation surgery at Washington University, St. Louis, and colleagues found.

The investigators looked at 1,629 patients diagnosed with HCC between Jan. 1, 2002, and Dec. 31, 2019 of whom 700 were considered for curative surgery, including transplant in 538, and resection in 162.

The patients had a mean age of 62.8 years. Those older than 65 years were less likely to be considered or listed for transplant (27% vs. 73%, P < .01), although oncologic staging and delisting rates were similar in both groups. “This observation still holds true after controlling for other variables, including viral hepatitis and gender in the multivariable analysis (adjusted odds ratio, 0.365),” the investigators reported in the Journal of the American College of Surgeons.

The findings were also reported at the 2020 virtual Western Surgical Association 128th Scientific Session in November.
 

The issue of resection

Surgical intervention occurred in 597 patients, including 392 and 205 aged 65 years and younger and over 65 years, respectively.

OS was lower among patients who underwent resection, compared with the liver transplant recipients, but was similar in the older and younger age groups (3-year OS, 59% vs. 64.8% and 5-year OS, 44.8% vs. 49%; P = .13). No differences were noted in the development of local or distant metastatic disease after transplant or resection.

The two age groups had comparable ICU stays (2 days) and total hospital length of stay (6 days). There were no differences in 30- and 90-day hospital readmissions, they noted.

“On additional age analysis, 65% of transplanted patients over 65 years are currently alive and were disease free at the end of the study period, compared to only 18% of their resected counterparts (P < .01),” they wrote.

Justifying transplant

The findings are notable because despite the effectiveness of transplant as an alternative treatment for unresectable HCC, older patients are often excluded from consideration for transplant. Most studies over the past 15 years have focused on patients aged under 60 years and the ability to extrapolate results to older patients has been limited. Further, results have been conflicting in older patients, the authors explained.

“This is particularly apposite at this time with prolonged life expectancy and the growing interest in improving cancer survivorship,” they noted, adding that “there is logic in challenging existing gold standards and traditional norms with real-life medical practice.

Indeed, the current findings suggest – perhaps contrary to common perceptions – that transplant in carefully selected patients “can be justified in older age groups and provide clinically meaningful and longer survival benefits,” they said, adding that “discussions should be guided by the potential for unfair age discriminations and precise terminology of physiologic rather than actual age.

“Such insights highlight the continued need for quality improvement in the surgical management of older patients, raising questions regarding current resource utilization among different age groups and how age can influence patterns of cancer care,” they concluded.

The authors reported having no disclosures.

[email protected]

Judicious organ matching for older liver transplant candidates with hepatocellular carcinoma (HCC) leads to survival outcomes similar to those in younger recipients, a case review suggests.

Overall survival (OS) rates among transplant recipients included in a prospective institutional database were 85.5% and 84% at 3 years after liver transplant in patients aged 65 years and under and those over 65 years, respectively. The 5-year survival rates were 73.9% and 77%, respectively (P = .26), Ola Ahmed, MD, of the department of abdominal organ transplantation surgery at Washington University, St. Louis, and colleagues found.

The investigators looked at 1,629 patients diagnosed with HCC between Jan. 1, 2002, and Dec. 31, 2019 of whom 700 were considered for curative surgery, including transplant in 538, and resection in 162.

The patients had a mean age of 62.8 years. Those older than 65 years were less likely to be considered or listed for transplant (27% vs. 73%, P < .01), although oncologic staging and delisting rates were similar in both groups. “This observation still holds true after controlling for other variables, including viral hepatitis and gender in the multivariable analysis (adjusted odds ratio, 0.365),” the investigators reported in the Journal of the American College of Surgeons.

The findings were also reported at the 2020 virtual Western Surgical Association 128th Scientific Session in November.
 

The issue of resection

Surgical intervention occurred in 597 patients, including 392 and 205 aged 65 years and younger and over 65 years, respectively.

OS was lower among patients who underwent resection, compared with the liver transplant recipients, but was similar in the older and younger age groups (3-year OS, 59% vs. 64.8% and 5-year OS, 44.8% vs. 49%; P = .13). No differences were noted in the development of local or distant metastatic disease after transplant or resection.

The two age groups had comparable ICU stays (2 days) and total hospital length of stay (6 days). There were no differences in 30- and 90-day hospital readmissions, they noted.

“On additional age analysis, 65% of transplanted patients over 65 years are currently alive and were disease free at the end of the study period, compared to only 18% of their resected counterparts (P < .01),” they wrote.

Justifying transplant

The findings are notable because despite the effectiveness of transplant as an alternative treatment for unresectable HCC, older patients are often excluded from consideration for transplant. Most studies over the past 15 years have focused on patients aged under 60 years and the ability to extrapolate results to older patients has been limited. Further, results have been conflicting in older patients, the authors explained.

“This is particularly apposite at this time with prolonged life expectancy and the growing interest in improving cancer survivorship,” they noted, adding that “there is logic in challenging existing gold standards and traditional norms with real-life medical practice.

Indeed, the current findings suggest – perhaps contrary to common perceptions – that transplant in carefully selected patients “can be justified in older age groups and provide clinically meaningful and longer survival benefits,” they said, adding that “discussions should be guided by the potential for unfair age discriminations and precise terminology of physiologic rather than actual age.

“Such insights highlight the continued need for quality improvement in the surgical management of older patients, raising questions regarding current resource utilization among different age groups and how age can influence patterns of cancer care,” they concluded.

The authors reported having no disclosures.

[email protected]

For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.

At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.

The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.

“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.

She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”

This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”

The study was published March 19, 2021, in Blood.
 

Curtailing steroids

Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.

In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.

The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.

S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”

He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.

“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
 

Improved event-free survival

In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.

The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.

The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.

With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)

The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).

Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).

Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).

The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.

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

For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.

At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.

The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.

“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.

She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”

This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”

The study was published March 19, 2021, in Blood.
 

Curtailing steroids

Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.

In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.

The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.

S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”

He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.

“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
 

Improved event-free survival

In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.

The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.

The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.

With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)

The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).

Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).

Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).

The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.

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

For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.

At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.

The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.

“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.

She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”

This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”

The study was published March 19, 2021, in Blood.
 

Curtailing steroids

Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.

In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.

The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.

S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”

He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.

“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
 

Improved event-free survival

In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.

The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.

The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.

With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)

The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).

Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).

Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).

The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.

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

Hematology-oncology patients who receive treatment in the intensive care unit often develop delirium, and according to new findings, mechanical ventilation, high-dose corticosteroid use, and brain metastases were identified as independent risk factors.

Roughly half of all hematology-oncology patients who were admitted to the ICU experienced delirium, explained lead author Rachel Klosko, PharmD, PGY-2 cardiology pharmacy resident at the Ohio State University, Columbus.

“Delirium was associated with increased mortality, an increase in hospital length of stay, and increased length of stay in the ICU,” she said.

Dr. Klosko presented the study results at the at the Critical Care Congress sponsored by the Society of Critical Care Medicine (SCCM), which was held virtually this year.

Delirium is an acute and fluctuating disturbance of consciousness and cognition and fluctuates in severity. Critically ill patients are subject to numerous risk factors for delirium. “It can occur in independently of any known neurological disorder,” said Dr. Klosko, adding that its occurrence has been associated with poorer outcomes in ICU patients.

In this study, Dr. Klosko and colleagues sought to determine the incidence of delirium in cancer patients who were admitted to the ICU, as well as identify the associated risk factors and recognize potential consequences of the development of delirium in this patient population.

They conducted a single center, retrospective, cohort study that evaluated patients between the ages of 18 and 89 years who were admitted to the hematology-oncology medical or surgical ICU between July 1, 2018, and June 30, 2019.

The study’s primary endpoint was the incidence of delirium within 7 days of ICU admission, defined as two positive Confusion Assessment Method for the ICU (CAM-ICU) assessments within 24 hours. Patients identified with delirium were compared to those without it, for the evaluation of secondary endpoints that included hospital mortality and ICU and hospital length of stay. The researchers also sought to identify independent risk factors for delirium in this population.

A total of 244 patients were included in the final analysis. Of this group, 125 (51.2%) experienced delirium during their stay in the ICU, and 119 (48.8%) did not.

Mortality in the delirium group was significantly higher at 32.8% vs. 15.1% (P = .001). In addition, the delirium group was associated with significantly higher ICU length of stay (6 days vs. 3 days, P < .001) and hospital length of stay (21 days vs. 12 days, P < .001).

“When comparing the baseline characteristics between the two groups, the delirium group had a longer hospital length prior to ICU admission, a higher SOFA score, a higher rate of brain metastases, a higher rate of shock, and higher receipt of high-dose steroids, benzodiazepines, and immunotherapy,” said Dr. Klosko.

After multivariable regression, four variables were included in the final model. Among patients with delirium, the SOFA score increased by 25% (odds ratio[OR] 1.25, P < .001), while the odds of delirium were almost four times higher among those treated with high-dose corticosteroids (OR 3.79, P = .004). Delirium was also eight times higher (OR 8.48, P < .001) among those who received mechanical ventilation and five times higher in (OR 5.38, P = .015) in patients with brain metastases.

Dr. Klosko noted that the main limitations for this study were that it was a single center retrospective analysis, and that patients were reviewed within the first 7 days of ICU admission. “This potentially missed patients who developed delirium outside of this time frame,” she said. In addition, “too few patients received high-dose benzodiazepines,” and “none of the patients received continuous neuromuscular blockade.”

However, in “contrast to these limitations, this is the largest study to date that has analyzed delirium in this population,” Dr. Klosko said.

Commenting on the study, Brenda Pun, DNP, RN, director of data quality at the Vanderbilt Critical Illness, Brain Dysfunction, and Survivorship Center, Nashville, Tenn., pointed out that the goal of this study was to describe delirium in this specific population. “But I will take a step backward and say that they are just confirming that these patients look like other ICU patients in many regards,” she said.

She explained that the sicker patients are, the higher the rates of delirium. “We have implemented strategies to lower these rates, and they have improved,” Dr. Pun said. “Ten years ago, I would say that 80% of patients who were on a ventilator would have delirium but now the rates are around 50% and that’s what we are typically seeing now.”

Dr. Pun emphasized that this study shows that delirium is like the “canary in the coal mine” or a red flag. “It’s a sign that something is wrong and that we need to pay attention, because the patient’s outcome may be worse,” she said. “So this is saying that we need to see if there is something that can be changed or modified to decrease the incidence of delirium—these are important questions.”

There was no outside sponsor. The authors had no disclosures. Dr. Pun has no disclosures.

Hematology-oncology patients who receive treatment in the intensive care unit often develop delirium, and according to new findings, mechanical ventilation, high-dose corticosteroid use, and brain metastases were identified as independent risk factors.

Roughly half of all hematology-oncology patients who were admitted to the ICU experienced delirium, explained lead author Rachel Klosko, PharmD, PGY-2 cardiology pharmacy resident at the Ohio State University, Columbus.

“Delirium was associated with increased mortality, an increase in hospital length of stay, and increased length of stay in the ICU,” she said.

Dr. Klosko presented the study results at the at the Critical Care Congress sponsored by the Society of Critical Care Medicine (SCCM), which was held virtually this year.

Delirium is an acute and fluctuating disturbance of consciousness and cognition and fluctuates in severity. Critically ill patients are subject to numerous risk factors for delirium. “It can occur in independently of any known neurological disorder,” said Dr. Klosko, adding that its occurrence has been associated with poorer outcomes in ICU patients.

In this study, Dr. Klosko and colleagues sought to determine the incidence of delirium in cancer patients who were admitted to the ICU, as well as identify the associated risk factors and recognize potential consequences of the development of delirium in this patient population.

They conducted a single center, retrospective, cohort study that evaluated patients between the ages of 18 and 89 years who were admitted to the hematology-oncology medical or surgical ICU between July 1, 2018, and June 30, 2019.

The study’s primary endpoint was the incidence of delirium within 7 days of ICU admission, defined as two positive Confusion Assessment Method for the ICU (CAM-ICU) assessments within 24 hours. Patients identified with delirium were compared to those without it, for the evaluation of secondary endpoints that included hospital mortality and ICU and hospital length of stay. The researchers also sought to identify independent risk factors for delirium in this population.

A total of 244 patients were included in the final analysis. Of this group, 125 (51.2%) experienced delirium during their stay in the ICU, and 119 (48.8%) did not.

Mortality in the delirium group was significantly higher at 32.8% vs. 15.1% (P = .001). In addition, the delirium group was associated with significantly higher ICU length of stay (6 days vs. 3 days, P < .001) and hospital length of stay (21 days vs. 12 days, P < .001).

“When comparing the baseline characteristics between the two groups, the delirium group had a longer hospital length prior to ICU admission, a higher SOFA score, a higher rate of brain metastases, a higher rate of shock, and higher receipt of high-dose steroids, benzodiazepines, and immunotherapy,” said Dr. Klosko.

After multivariable regression, four variables were included in the final model. Among patients with delirium, the SOFA score increased by 25% (odds ratio[OR] 1.25, P < .001), while the odds of delirium were almost four times higher among those treated with high-dose corticosteroids (OR 3.79, P = .004). Delirium was also eight times higher (OR 8.48, P < .001) among those who received mechanical ventilation and five times higher in (OR 5.38, P = .015) in patients with brain metastases.

Dr. Klosko noted that the main limitations for this study were that it was a single center retrospective analysis, and that patients were reviewed within the first 7 days of ICU admission. “This potentially missed patients who developed delirium outside of this time frame,” she said. In addition, “too few patients received high-dose benzodiazepines,” and “none of the patients received continuous neuromuscular blockade.”

However, in “contrast to these limitations, this is the largest study to date that has analyzed delirium in this population,” Dr. Klosko said.

Commenting on the study, Brenda Pun, DNP, RN, director of data quality at the Vanderbilt Critical Illness, Brain Dysfunction, and Survivorship Center, Nashville, Tenn., pointed out that the goal of this study was to describe delirium in this specific population. “But I will take a step backward and say that they are just confirming that these patients look like other ICU patients in many regards,” she said.

She explained that the sicker patients are, the higher the rates of delirium. “We have implemented strategies to lower these rates, and they have improved,” Dr. Pun said. “Ten years ago, I would say that 80% of patients who were on a ventilator would have delirium but now the rates are around 50% and that’s what we are typically seeing now.”

Dr. Pun emphasized that this study shows that delirium is like the “canary in the coal mine” or a red flag. “It’s a sign that something is wrong and that we need to pay attention, because the patient’s outcome may be worse,” she said. “So this is saying that we need to see if there is something that can be changed or modified to decrease the incidence of delirium—these are important questions.”

There was no outside sponsor. The authors had no disclosures. Dr. Pun has no disclosures.

Hematology-oncology patients who receive treatment in the intensive care unit often develop delirium, and according to new findings, mechanical ventilation, high-dose corticosteroid use, and brain metastases were identified as independent risk factors.

Roughly half of all hematology-oncology patients who were admitted to the ICU experienced delirium, explained lead author Rachel Klosko, PharmD, PGY-2 cardiology pharmacy resident at the Ohio State University, Columbus.

“Delirium was associated with increased mortality, an increase in hospital length of stay, and increased length of stay in the ICU,” she said.

Dr. Klosko presented the study results at the at the Critical Care Congress sponsored by the Society of Critical Care Medicine (SCCM), which was held virtually this year.

Delirium is an acute and fluctuating disturbance of consciousness and cognition and fluctuates in severity. Critically ill patients are subject to numerous risk factors for delirium. “It can occur in independently of any known neurological disorder,” said Dr. Klosko, adding that its occurrence has been associated with poorer outcomes in ICU patients.

In this study, Dr. Klosko and colleagues sought to determine the incidence of delirium in cancer patients who were admitted to the ICU, as well as identify the associated risk factors and recognize potential consequences of the development of delirium in this patient population.

They conducted a single center, retrospective, cohort study that evaluated patients between the ages of 18 and 89 years who were admitted to the hematology-oncology medical or surgical ICU between July 1, 2018, and June 30, 2019.

The study’s primary endpoint was the incidence of delirium within 7 days of ICU admission, defined as two positive Confusion Assessment Method for the ICU (CAM-ICU) assessments within 24 hours. Patients identified with delirium were compared to those without it, for the evaluation of secondary endpoints that included hospital mortality and ICU and hospital length of stay. The researchers also sought to identify independent risk factors for delirium in this population.

A total of 244 patients were included in the final analysis. Of this group, 125 (51.2%) experienced delirium during their stay in the ICU, and 119 (48.8%) did not.

Mortality in the delirium group was significantly higher at 32.8% vs. 15.1% (P = .001). In addition, the delirium group was associated with significantly higher ICU length of stay (6 days vs. 3 days, P < .001) and hospital length of stay (21 days vs. 12 days, P < .001).

“When comparing the baseline characteristics between the two groups, the delirium group had a longer hospital length prior to ICU admission, a higher SOFA score, a higher rate of brain metastases, a higher rate of shock, and higher receipt of high-dose steroids, benzodiazepines, and immunotherapy,” said Dr. Klosko.

After multivariable regression, four variables were included in the final model. Among patients with delirium, the SOFA score increased by 25% (odds ratio[OR] 1.25, P < .001), while the odds of delirium were almost four times higher among those treated with high-dose corticosteroids (OR 3.79, P = .004). Delirium was also eight times higher (OR 8.48, P < .001) among those who received mechanical ventilation and five times higher in (OR 5.38, P = .015) in patients with brain metastases.

Dr. Klosko noted that the main limitations for this study were that it was a single center retrospective analysis, and that patients were reviewed within the first 7 days of ICU admission. “This potentially missed patients who developed delirium outside of this time frame,” she said. In addition, “too few patients received high-dose benzodiazepines,” and “none of the patients received continuous neuromuscular blockade.”

However, in “contrast to these limitations, this is the largest study to date that has analyzed delirium in this population,” Dr. Klosko said.

Commenting on the study, Brenda Pun, DNP, RN, director of data quality at the Vanderbilt Critical Illness, Brain Dysfunction, and Survivorship Center, Nashville, Tenn., pointed out that the goal of this study was to describe delirium in this specific population. “But I will take a step backward and say that they are just confirming that these patients look like other ICU patients in many regards,” she said.

She explained that the sicker patients are, the higher the rates of delirium. “We have implemented strategies to lower these rates, and they have improved,” Dr. Pun said. “Ten years ago, I would say that 80% of patients who were on a ventilator would have delirium but now the rates are around 50% and that’s what we are typically seeing now.”

Dr. Pun emphasized that this study shows that delirium is like the “canary in the coal mine” or a red flag. “It’s a sign that something is wrong and that we need to pay attention, because the patient’s outcome may be worse,” she said. “So this is saying that we need to see if there is something that can be changed or modified to decrease the incidence of delirium—these are important questions.”

There was no outside sponsor. The authors had no disclosures. Dr. Pun has no disclosures.