User login
Treatment for pediatric low-grade glioma is associated with poor cognitive and socioeconomic outcomes
Children who underwent surgery alone had better neuropsychologic and socioeconomic outcomes than those who also underwent radiotherapy, but their outcomes were worse than those of unaffected siblings. These findings were published online June 24 in Cancer.
“Late effects in adulthood are evident even for children with the least malignant types of brain tumors who were treated with the least toxic therapies available at the time,” said M. Douglas Ris, PhD, professor of pediatrics and psychology at Baylor College of Medicine in Houston, in a press release. “As pediatric brain tumors become more survivable with continued advances in treatments, we need to improve surveillance of these populations so that survivors continue to receive the best interventions during their transition to adulthood and well beyond.”
Clinicians generally have assumed that children with low-grade CNS tumors who receive less toxic treatment will have fewer long-term effects than survivors of more malignant tumors who undergo neurotoxic therapies. Yet research has indicated that the former patients can have lasting neurobehavioral or functional morbidity.
Dr. Ris and colleagues invited survivors of pediatric low-grade gliomas participating in the Childhood Cancer Survivor Study (CCSS) and a sibling comparison group to undergo a direct, comprehensive neurocognitive assessment. Of 495 eligible survivors, 257 participated. Seventy-six patients did not travel to a study site, but completed a questionnaire, and the researchers did not include data for this group in their analysis. Dr. Ris and colleagues obtained information about surgery and radiotherapy from participants’ medical records. Patients underwent standardized, age-normed neuropsychologic tests. The primary neuropsychologic outcomes were the Composite Neuropsychological Index (CNI) and estimated IQ. To evaluate socioeconomic outcomes, Dr. Ris and colleagues measured participants’ educational attainment, income, and occupational prestige.
After the researchers adjusted the data for age and sex, they found that siblings had higher mean scores than survivors treated with surgery plus radiotherapy or surgery alone on all neuropsychologic outcomes, including the CNI (siblings, 106.8; surgery only, 95.6; surgery plus radiotherapy, 88.3) and estimated IQ. Survivors who had been diagnosed at younger ages had low scores for all outcomes except for attention/processing speed.
Furthermore, surgery plus radiotherapy was associated with a 7.7-fold higher risk of having an occupation in the lowest sibling quartile, compared with siblings. Survivors who underwent surgery alone had a 2.8-fold higher risk than siblings of having an occupation in the lowest quartile. Surgery plus radiotherapy was associated with a 2.6-fold increased risk of a low occupation score, compared with survivors who underwent surgery alone.
Compared with siblings, surgery plus radiotherapy was associated with a 4.5-fold risk of an annual income of less than $20,000, while the risk for survivors who underwent surgery alone did not differ significantly from that for siblings. Surgery plus radiotherapy was associated with a 2.6-fold higher risk than surgery alone. Surgery plus radiotherapy was also associated with a significantly increased risk for an education level lower than a bachelor’s degree, compared with siblings, but surgery alone was not.
The National Cancer Institute supported the study. The authors had no disclosures.
SOURCE: Ris MD et al. Cancer. 2019 Jun 24. doi: 10.1002/cncr.32186.
Children who underwent surgery alone had better neuropsychologic and socioeconomic outcomes than those who also underwent radiotherapy, but their outcomes were worse than those of unaffected siblings. These findings were published online June 24 in Cancer.
“Late effects in adulthood are evident even for children with the least malignant types of brain tumors who were treated with the least toxic therapies available at the time,” said M. Douglas Ris, PhD, professor of pediatrics and psychology at Baylor College of Medicine in Houston, in a press release. “As pediatric brain tumors become more survivable with continued advances in treatments, we need to improve surveillance of these populations so that survivors continue to receive the best interventions during their transition to adulthood and well beyond.”
Clinicians generally have assumed that children with low-grade CNS tumors who receive less toxic treatment will have fewer long-term effects than survivors of more malignant tumors who undergo neurotoxic therapies. Yet research has indicated that the former patients can have lasting neurobehavioral or functional morbidity.
Dr. Ris and colleagues invited survivors of pediatric low-grade gliomas participating in the Childhood Cancer Survivor Study (CCSS) and a sibling comparison group to undergo a direct, comprehensive neurocognitive assessment. Of 495 eligible survivors, 257 participated. Seventy-six patients did not travel to a study site, but completed a questionnaire, and the researchers did not include data for this group in their analysis. Dr. Ris and colleagues obtained information about surgery and radiotherapy from participants’ medical records. Patients underwent standardized, age-normed neuropsychologic tests. The primary neuropsychologic outcomes were the Composite Neuropsychological Index (CNI) and estimated IQ. To evaluate socioeconomic outcomes, Dr. Ris and colleagues measured participants’ educational attainment, income, and occupational prestige.
After the researchers adjusted the data for age and sex, they found that siblings had higher mean scores than survivors treated with surgery plus radiotherapy or surgery alone on all neuropsychologic outcomes, including the CNI (siblings, 106.8; surgery only, 95.6; surgery plus radiotherapy, 88.3) and estimated IQ. Survivors who had been diagnosed at younger ages had low scores for all outcomes except for attention/processing speed.
Furthermore, surgery plus radiotherapy was associated with a 7.7-fold higher risk of having an occupation in the lowest sibling quartile, compared with siblings. Survivors who underwent surgery alone had a 2.8-fold higher risk than siblings of having an occupation in the lowest quartile. Surgery plus radiotherapy was associated with a 2.6-fold increased risk of a low occupation score, compared with survivors who underwent surgery alone.
Compared with siblings, surgery plus radiotherapy was associated with a 4.5-fold risk of an annual income of less than $20,000, while the risk for survivors who underwent surgery alone did not differ significantly from that for siblings. Surgery plus radiotherapy was associated with a 2.6-fold higher risk than surgery alone. Surgery plus radiotherapy was also associated with a significantly increased risk for an education level lower than a bachelor’s degree, compared with siblings, but surgery alone was not.
The National Cancer Institute supported the study. The authors had no disclosures.
SOURCE: Ris MD et al. Cancer. 2019 Jun 24. doi: 10.1002/cncr.32186.
Children who underwent surgery alone had better neuropsychologic and socioeconomic outcomes than those who also underwent radiotherapy, but their outcomes were worse than those of unaffected siblings. These findings were published online June 24 in Cancer.
“Late effects in adulthood are evident even for children with the least malignant types of brain tumors who were treated with the least toxic therapies available at the time,” said M. Douglas Ris, PhD, professor of pediatrics and psychology at Baylor College of Medicine in Houston, in a press release. “As pediatric brain tumors become more survivable with continued advances in treatments, we need to improve surveillance of these populations so that survivors continue to receive the best interventions during their transition to adulthood and well beyond.”
Clinicians generally have assumed that children with low-grade CNS tumors who receive less toxic treatment will have fewer long-term effects than survivors of more malignant tumors who undergo neurotoxic therapies. Yet research has indicated that the former patients can have lasting neurobehavioral or functional morbidity.
Dr. Ris and colleagues invited survivors of pediatric low-grade gliomas participating in the Childhood Cancer Survivor Study (CCSS) and a sibling comparison group to undergo a direct, comprehensive neurocognitive assessment. Of 495 eligible survivors, 257 participated. Seventy-six patients did not travel to a study site, but completed a questionnaire, and the researchers did not include data for this group in their analysis. Dr. Ris and colleagues obtained information about surgery and radiotherapy from participants’ medical records. Patients underwent standardized, age-normed neuropsychologic tests. The primary neuropsychologic outcomes were the Composite Neuropsychological Index (CNI) and estimated IQ. To evaluate socioeconomic outcomes, Dr. Ris and colleagues measured participants’ educational attainment, income, and occupational prestige.
After the researchers adjusted the data for age and sex, they found that siblings had higher mean scores than survivors treated with surgery plus radiotherapy or surgery alone on all neuropsychologic outcomes, including the CNI (siblings, 106.8; surgery only, 95.6; surgery plus radiotherapy, 88.3) and estimated IQ. Survivors who had been diagnosed at younger ages had low scores for all outcomes except for attention/processing speed.
Furthermore, surgery plus radiotherapy was associated with a 7.7-fold higher risk of having an occupation in the lowest sibling quartile, compared with siblings. Survivors who underwent surgery alone had a 2.8-fold higher risk than siblings of having an occupation in the lowest quartile. Surgery plus radiotherapy was associated with a 2.6-fold increased risk of a low occupation score, compared with survivors who underwent surgery alone.
Compared with siblings, surgery plus radiotherapy was associated with a 4.5-fold risk of an annual income of less than $20,000, while the risk for survivors who underwent surgery alone did not differ significantly from that for siblings. Surgery plus radiotherapy was associated with a 2.6-fold higher risk than surgery alone. Surgery plus radiotherapy was also associated with a significantly increased risk for an education level lower than a bachelor’s degree, compared with siblings, but surgery alone was not.
The National Cancer Institute supported the study. The authors had no disclosures.
SOURCE: Ris MD et al. Cancer. 2019 Jun 24. doi: 10.1002/cncr.32186.
FROM CANCER
Affiliate cancer centers: What’s in a name?
Daniel Boffa, MD, was never able to shake the unfortunate incident from his mind. An acquaintance receiving cancer care at an affiliate center of a top-ranked cancer hospital had experienced a poor, and possibly preventable, outcome.
“As I learned more about the outcome, it became clear to me that the affiliate wasn’t prepared to handle a complication that was not unexpected,” said Dr. Boffa, a thoracic surgeon at Yale Cancer Center in New Haven, Conn. “When I talked to this individual and the people who helped make the decision for where care was going to be given, they kept saying over and over, ‘It says the name of a top-ranked hospital on the sign [of the affiliate], therefore it’s the same.’ ”
The incident compelled Dr. Boffa and colleagues to learn more about the safety at affiliate cancer centers. The result is an analysis that found that patients who underwent complex cancer surgery at affiliate hospitals were significantly more likely to die within 90 days, compared with patients receiving the same surgery at the flagship hospital. When the relative safety of each top-ranked cancer hospital was compared with its collective affiliates, the top-ranked hospital was safer than affiliates in 41 of 49 networks studied (JAMA Netw Open. 2019 Apr 12. doi: 10.1001/jamanetworkopen.2019.1912).
The analysis illustrates that a patient’s chances of surviving a complex cancer surgery are markedly lower at affiliates, compared with the hospital whose brand it shares, Dr. Boffa explained.
“Every patient and everybody that is supporting a patient in making these [care] decisions can’t assume the care is the same,” he said. “This is not to say that the affiliates are unsafe, they are just less safe than the top-ranked hospitals.”
The findings come as more top-ranked cancer hospital align with affiliate cancer centers and grow partnerships with smaller, community hospitals.
Leaders at these institutions say the partnerships expand access to care and enable regional centers to draw from the expertise at specialized cancer hospitals. However, in addition to safety concerns, the recent data pose questions about whether marketing by some institutions is creating inaccurate perceptions about the relationship between top hospitals and their affiliates. At the same time, it’s uncertain whether network affiliations really improve cost or quality, said Lesly Dossett, MD, an oncologist and researcher at the University of Michigan, Ann Arbor.
“Affiliation has the theoretical advantage of improving efficiency and quality across hospitals and facilitating regionalization of the most complex patients,” said Dr. Dossett, who wrote a commentary for JAMA on the subject. “An ideal network would provide the patient the most convenient access to the right specialist and service at the right time. Disadvantages are that patients and families can attribute quality and safety outcomes achieved at the flagship hospital to the smaller branded affiliate and decline to travel to the flagship, even though some services, like complex surgery, may be best delivered at the flagship.”
What’s an affiliate?
Part of the problem is the ambiguity surrounding the many different relationships among top-ranked cancer hospitals and associated institutions, said J. Leonard Lichtenfeld, MD, interim chief medical officer for the American Cancer Society. In some cases, the primary institution is closely aligned with an affiliate, sharing staff and collaborating on patient cases. In other instances, a reputable hospital offers its brand to a hospital in a distant location, and the relationship is more marketing and information-sharing based.
“Just because a name shows up on a building, doesn’t necessarily mean the same level of care is being provided at an affiliated institution,” Dr. Lichtenfeld said. “There are factors that neither you nor me can look into to determine how close the affiliation is. Sometimes, it can be a very tight relationship. Sometimes it can be a loose relationship, and it’s very hard to figure that out.”
In a survey of 1,010 patients, 94% of respondents felt that cancer care at a smaller hospital would improve after affiliating with a larger hospital specializing in cancer, and most patients expected physicians at the larger hospital to be involved considerably in the care of patients at the smaller hospital after affiliation (JAMA Oncol. 2018;4[7]:1008-9).
In another survey, 85% of patients said they would rather travel an hour for complex surgery at a larger hospital specializing in cancer, rather than a smaller local hospital. However, if the smaller hospital was affiliated with a top-ranked cancer hospital, 31% of respondents changed their preference to the smaller hospital, according to the analysis (Ann Surg Oncol. 2019 Mar;26[3]:732-8).
When asked to compare leading cancer hospitals and their smaller affiliates, 47% of respondents said they felt that surgical safety would be the same at both hospitals, 66% said that guideline compliance would be the same, and 53% of patients said they believed that cure rates would be the same at both institutions.
“A majority of the public feels when the brand is shared between a top-ranked hospital and a hospital in the community, the quality and safety is the same,” said Dr. Boffa, a coauthor of both survey studies. “The advertising differs for each affiliate, but there are certainly instances where the messaging can be misinterpreted. There are instances where there are billboards and advertisements where the implication is the community hospital to some degree has care that is similar to the main hospital.”
Hospitals: Collaborations beneficial
For the University of Wisconsin–Madison (UW) Carbone Cancer Center, its relationships with several community institutions have enhanced consistency among physician teams and provided new care opportunities for patients, said Dan Mulkerin, MD, regional director of UW’s regional cancer center network. Carbone includes 12 locales of service and four affiliates in various stages of maturity.
In some cases, UW physicians travel to the affiliate to help care for patients but refer surgeries back to the main institution. In other cases, UW surgical specialists operate jointly with local surgeons at the community hospital, according to Dr. Mulkerin.
The surgical safety of affiliates is an issue that UW started to address about 5 years ago, he said.
“We recognized that this was a potential area of concern for our cancer programs and we started incorporating surgical oncology into our affiliate structure,” Dr. Mulkerin said. “We look at the quality outcomes of our partners on a quarterly basis. That drives our approach about which types of surgery gets triaged to come to the main institution and which types of surgeries can appropriately be done in community settings under our brand, and under our guidance.”
At H. Lee Moffitt Cancer Center & Research Institute, physicians travel from the headquarters to its partner hospitals to deliver care and work with doctors at each site. For example, Moffitt leaders are overseeing a program with Memorial Healthcare System in South Florida that focuses on malignant hematology and blood and marrow transplantation, said Louis Harrison, MD, chair for Moffitt’s radiation oncology department and vice president, chief partnership officer.
“These are real partnerships where we put our faculty and our know-how on the ground at these sites,” he said in an interview. “We feel like the only way to deliver care that is representative to Moffitt is to have Moffitt doctors deliver the care.”
The University of Texas MD Anderson Cancer Center, Houston, meanwhile, boasts a robust network of partner members, certified member hospitals, associate members, and affiliates. Partner members are U.S.-based relationships where member health systems integrate their clinical cancer care operations with MD Anderson, said Michael Kupferman, MD, senior vice president of clinical and academic network development at MD Anderson. Certified members receive assessments by MD Anderson and tailored recommendations for clinical quality improvements, while associate members stem from international clinical relationships with MD Anderson. Affiliates have a relationship with MD Anderson in one specialty- or modality-focused area, such as radiation oncology.
“All MD Anderson Cancer Network members operate independently from MD Anderson Cancer Center,” Dr. Kupferman said in an interview. “All cancer network members have access to our expertise and clinical knowledge to improve the level of cancer care in their communities.”
In terms of marketing the different types of network members, Dr. Kupferman said that MD Anderson collaborates with members on internal and external marketing and communications strategies to offer “best practices and guidance on how to best educate the alignment and benefits of the relationship to internal staff and local communities.”
Dr. Kupferman declined to directly comment on how surgical safety at MD Anderson’s member institutions is addressed or respond to the JAMA study findings. “We believe that our cancer network members strive to practice at a level higher than the national safety average, as evidenced by the consistent quality reviews we conduct with our members.”
An opportunity to improve
A key advantage to affiliate cancer centers is the expanded care access they can provide to patients, said Dr. Lichtenfeld. While some patients can bypass their community hospital and travel to a top-ranked cancer hospital for treatment, others do not have that capability.
“Some people will not leave their communities,” he said. “It would be wrong to take this research and point at bad doctors for not sending their patient [to a more specialized hospital]. Sometimes, its patients themselves, by choice or necessity, who can’t go somewhere else.”
Dr. Boffa emphasized that the recent research on safety presents an exciting opportunity for flagship institutions and their affiliates to analyze their structure and make improvements where necessary.
“The fact that [the hospitals] are already connected in some way is a huge advance; that’s half the battle,” Dr. Boffa said. “The next step is how do we distill what elements of care are transferable. How do we leverage this connection to share what makes the safer hospitals safer?”
Daniel Boffa, MD, was never able to shake the unfortunate incident from his mind. An acquaintance receiving cancer care at an affiliate center of a top-ranked cancer hospital had experienced a poor, and possibly preventable, outcome.
“As I learned more about the outcome, it became clear to me that the affiliate wasn’t prepared to handle a complication that was not unexpected,” said Dr. Boffa, a thoracic surgeon at Yale Cancer Center in New Haven, Conn. “When I talked to this individual and the people who helped make the decision for where care was going to be given, they kept saying over and over, ‘It says the name of a top-ranked hospital on the sign [of the affiliate], therefore it’s the same.’ ”
The incident compelled Dr. Boffa and colleagues to learn more about the safety at affiliate cancer centers. The result is an analysis that found that patients who underwent complex cancer surgery at affiliate hospitals were significantly more likely to die within 90 days, compared with patients receiving the same surgery at the flagship hospital. When the relative safety of each top-ranked cancer hospital was compared with its collective affiliates, the top-ranked hospital was safer than affiliates in 41 of 49 networks studied (JAMA Netw Open. 2019 Apr 12. doi: 10.1001/jamanetworkopen.2019.1912).
The analysis illustrates that a patient’s chances of surviving a complex cancer surgery are markedly lower at affiliates, compared with the hospital whose brand it shares, Dr. Boffa explained.
“Every patient and everybody that is supporting a patient in making these [care] decisions can’t assume the care is the same,” he said. “This is not to say that the affiliates are unsafe, they are just less safe than the top-ranked hospitals.”
The findings come as more top-ranked cancer hospital align with affiliate cancer centers and grow partnerships with smaller, community hospitals.
Leaders at these institutions say the partnerships expand access to care and enable regional centers to draw from the expertise at specialized cancer hospitals. However, in addition to safety concerns, the recent data pose questions about whether marketing by some institutions is creating inaccurate perceptions about the relationship between top hospitals and their affiliates. At the same time, it’s uncertain whether network affiliations really improve cost or quality, said Lesly Dossett, MD, an oncologist and researcher at the University of Michigan, Ann Arbor.
“Affiliation has the theoretical advantage of improving efficiency and quality across hospitals and facilitating regionalization of the most complex patients,” said Dr. Dossett, who wrote a commentary for JAMA on the subject. “An ideal network would provide the patient the most convenient access to the right specialist and service at the right time. Disadvantages are that patients and families can attribute quality and safety outcomes achieved at the flagship hospital to the smaller branded affiliate and decline to travel to the flagship, even though some services, like complex surgery, may be best delivered at the flagship.”
What’s an affiliate?
Part of the problem is the ambiguity surrounding the many different relationships among top-ranked cancer hospitals and associated institutions, said J. Leonard Lichtenfeld, MD, interim chief medical officer for the American Cancer Society. In some cases, the primary institution is closely aligned with an affiliate, sharing staff and collaborating on patient cases. In other instances, a reputable hospital offers its brand to a hospital in a distant location, and the relationship is more marketing and information-sharing based.
“Just because a name shows up on a building, doesn’t necessarily mean the same level of care is being provided at an affiliated institution,” Dr. Lichtenfeld said. “There are factors that neither you nor me can look into to determine how close the affiliation is. Sometimes, it can be a very tight relationship. Sometimes it can be a loose relationship, and it’s very hard to figure that out.”
In a survey of 1,010 patients, 94% of respondents felt that cancer care at a smaller hospital would improve after affiliating with a larger hospital specializing in cancer, and most patients expected physicians at the larger hospital to be involved considerably in the care of patients at the smaller hospital after affiliation (JAMA Oncol. 2018;4[7]:1008-9).
In another survey, 85% of patients said they would rather travel an hour for complex surgery at a larger hospital specializing in cancer, rather than a smaller local hospital. However, if the smaller hospital was affiliated with a top-ranked cancer hospital, 31% of respondents changed their preference to the smaller hospital, according to the analysis (Ann Surg Oncol. 2019 Mar;26[3]:732-8).
When asked to compare leading cancer hospitals and their smaller affiliates, 47% of respondents said they felt that surgical safety would be the same at both hospitals, 66% said that guideline compliance would be the same, and 53% of patients said they believed that cure rates would be the same at both institutions.
“A majority of the public feels when the brand is shared between a top-ranked hospital and a hospital in the community, the quality and safety is the same,” said Dr. Boffa, a coauthor of both survey studies. “The advertising differs for each affiliate, but there are certainly instances where the messaging can be misinterpreted. There are instances where there are billboards and advertisements where the implication is the community hospital to some degree has care that is similar to the main hospital.”
Hospitals: Collaborations beneficial
For the University of Wisconsin–Madison (UW) Carbone Cancer Center, its relationships with several community institutions have enhanced consistency among physician teams and provided new care opportunities for patients, said Dan Mulkerin, MD, regional director of UW’s regional cancer center network. Carbone includes 12 locales of service and four affiliates in various stages of maturity.
In some cases, UW physicians travel to the affiliate to help care for patients but refer surgeries back to the main institution. In other cases, UW surgical specialists operate jointly with local surgeons at the community hospital, according to Dr. Mulkerin.
The surgical safety of affiliates is an issue that UW started to address about 5 years ago, he said.
“We recognized that this was a potential area of concern for our cancer programs and we started incorporating surgical oncology into our affiliate structure,” Dr. Mulkerin said. “We look at the quality outcomes of our partners on a quarterly basis. That drives our approach about which types of surgery gets triaged to come to the main institution and which types of surgeries can appropriately be done in community settings under our brand, and under our guidance.”
At H. Lee Moffitt Cancer Center & Research Institute, physicians travel from the headquarters to its partner hospitals to deliver care and work with doctors at each site. For example, Moffitt leaders are overseeing a program with Memorial Healthcare System in South Florida that focuses on malignant hematology and blood and marrow transplantation, said Louis Harrison, MD, chair for Moffitt’s radiation oncology department and vice president, chief partnership officer.
“These are real partnerships where we put our faculty and our know-how on the ground at these sites,” he said in an interview. “We feel like the only way to deliver care that is representative to Moffitt is to have Moffitt doctors deliver the care.”
The University of Texas MD Anderson Cancer Center, Houston, meanwhile, boasts a robust network of partner members, certified member hospitals, associate members, and affiliates. Partner members are U.S.-based relationships where member health systems integrate their clinical cancer care operations with MD Anderson, said Michael Kupferman, MD, senior vice president of clinical and academic network development at MD Anderson. Certified members receive assessments by MD Anderson and tailored recommendations for clinical quality improvements, while associate members stem from international clinical relationships with MD Anderson. Affiliates have a relationship with MD Anderson in one specialty- or modality-focused area, such as radiation oncology.
“All MD Anderson Cancer Network members operate independently from MD Anderson Cancer Center,” Dr. Kupferman said in an interview. “All cancer network members have access to our expertise and clinical knowledge to improve the level of cancer care in their communities.”
In terms of marketing the different types of network members, Dr. Kupferman said that MD Anderson collaborates with members on internal and external marketing and communications strategies to offer “best practices and guidance on how to best educate the alignment and benefits of the relationship to internal staff and local communities.”
Dr. Kupferman declined to directly comment on how surgical safety at MD Anderson’s member institutions is addressed or respond to the JAMA study findings. “We believe that our cancer network members strive to practice at a level higher than the national safety average, as evidenced by the consistent quality reviews we conduct with our members.”
An opportunity to improve
A key advantage to affiliate cancer centers is the expanded care access they can provide to patients, said Dr. Lichtenfeld. While some patients can bypass their community hospital and travel to a top-ranked cancer hospital for treatment, others do not have that capability.
“Some people will not leave their communities,” he said. “It would be wrong to take this research and point at bad doctors for not sending their patient [to a more specialized hospital]. Sometimes, its patients themselves, by choice or necessity, who can’t go somewhere else.”
Dr. Boffa emphasized that the recent research on safety presents an exciting opportunity for flagship institutions and their affiliates to analyze their structure and make improvements where necessary.
“The fact that [the hospitals] are already connected in some way is a huge advance; that’s half the battle,” Dr. Boffa said. “The next step is how do we distill what elements of care are transferable. How do we leverage this connection to share what makes the safer hospitals safer?”
Daniel Boffa, MD, was never able to shake the unfortunate incident from his mind. An acquaintance receiving cancer care at an affiliate center of a top-ranked cancer hospital had experienced a poor, and possibly preventable, outcome.
“As I learned more about the outcome, it became clear to me that the affiliate wasn’t prepared to handle a complication that was not unexpected,” said Dr. Boffa, a thoracic surgeon at Yale Cancer Center in New Haven, Conn. “When I talked to this individual and the people who helped make the decision for where care was going to be given, they kept saying over and over, ‘It says the name of a top-ranked hospital on the sign [of the affiliate], therefore it’s the same.’ ”
The incident compelled Dr. Boffa and colleagues to learn more about the safety at affiliate cancer centers. The result is an analysis that found that patients who underwent complex cancer surgery at affiliate hospitals were significantly more likely to die within 90 days, compared with patients receiving the same surgery at the flagship hospital. When the relative safety of each top-ranked cancer hospital was compared with its collective affiliates, the top-ranked hospital was safer than affiliates in 41 of 49 networks studied (JAMA Netw Open. 2019 Apr 12. doi: 10.1001/jamanetworkopen.2019.1912).
The analysis illustrates that a patient’s chances of surviving a complex cancer surgery are markedly lower at affiliates, compared with the hospital whose brand it shares, Dr. Boffa explained.
“Every patient and everybody that is supporting a patient in making these [care] decisions can’t assume the care is the same,” he said. “This is not to say that the affiliates are unsafe, they are just less safe than the top-ranked hospitals.”
The findings come as more top-ranked cancer hospital align with affiliate cancer centers and grow partnerships with smaller, community hospitals.
Leaders at these institutions say the partnerships expand access to care and enable regional centers to draw from the expertise at specialized cancer hospitals. However, in addition to safety concerns, the recent data pose questions about whether marketing by some institutions is creating inaccurate perceptions about the relationship between top hospitals and their affiliates. At the same time, it’s uncertain whether network affiliations really improve cost or quality, said Lesly Dossett, MD, an oncologist and researcher at the University of Michigan, Ann Arbor.
“Affiliation has the theoretical advantage of improving efficiency and quality across hospitals and facilitating regionalization of the most complex patients,” said Dr. Dossett, who wrote a commentary for JAMA on the subject. “An ideal network would provide the patient the most convenient access to the right specialist and service at the right time. Disadvantages are that patients and families can attribute quality and safety outcomes achieved at the flagship hospital to the smaller branded affiliate and decline to travel to the flagship, even though some services, like complex surgery, may be best delivered at the flagship.”
What’s an affiliate?
Part of the problem is the ambiguity surrounding the many different relationships among top-ranked cancer hospitals and associated institutions, said J. Leonard Lichtenfeld, MD, interim chief medical officer for the American Cancer Society. In some cases, the primary institution is closely aligned with an affiliate, sharing staff and collaborating on patient cases. In other instances, a reputable hospital offers its brand to a hospital in a distant location, and the relationship is more marketing and information-sharing based.
“Just because a name shows up on a building, doesn’t necessarily mean the same level of care is being provided at an affiliated institution,” Dr. Lichtenfeld said. “There are factors that neither you nor me can look into to determine how close the affiliation is. Sometimes, it can be a very tight relationship. Sometimes it can be a loose relationship, and it’s very hard to figure that out.”
In a survey of 1,010 patients, 94% of respondents felt that cancer care at a smaller hospital would improve after affiliating with a larger hospital specializing in cancer, and most patients expected physicians at the larger hospital to be involved considerably in the care of patients at the smaller hospital after affiliation (JAMA Oncol. 2018;4[7]:1008-9).
In another survey, 85% of patients said they would rather travel an hour for complex surgery at a larger hospital specializing in cancer, rather than a smaller local hospital. However, if the smaller hospital was affiliated with a top-ranked cancer hospital, 31% of respondents changed their preference to the smaller hospital, according to the analysis (Ann Surg Oncol. 2019 Mar;26[3]:732-8).
When asked to compare leading cancer hospitals and their smaller affiliates, 47% of respondents said they felt that surgical safety would be the same at both hospitals, 66% said that guideline compliance would be the same, and 53% of patients said they believed that cure rates would be the same at both institutions.
“A majority of the public feels when the brand is shared between a top-ranked hospital and a hospital in the community, the quality and safety is the same,” said Dr. Boffa, a coauthor of both survey studies. “The advertising differs for each affiliate, but there are certainly instances where the messaging can be misinterpreted. There are instances where there are billboards and advertisements where the implication is the community hospital to some degree has care that is similar to the main hospital.”
Hospitals: Collaborations beneficial
For the University of Wisconsin–Madison (UW) Carbone Cancer Center, its relationships with several community institutions have enhanced consistency among physician teams and provided new care opportunities for patients, said Dan Mulkerin, MD, regional director of UW’s regional cancer center network. Carbone includes 12 locales of service and four affiliates in various stages of maturity.
In some cases, UW physicians travel to the affiliate to help care for patients but refer surgeries back to the main institution. In other cases, UW surgical specialists operate jointly with local surgeons at the community hospital, according to Dr. Mulkerin.
The surgical safety of affiliates is an issue that UW started to address about 5 years ago, he said.
“We recognized that this was a potential area of concern for our cancer programs and we started incorporating surgical oncology into our affiliate structure,” Dr. Mulkerin said. “We look at the quality outcomes of our partners on a quarterly basis. That drives our approach about which types of surgery gets triaged to come to the main institution and which types of surgeries can appropriately be done in community settings under our brand, and under our guidance.”
At H. Lee Moffitt Cancer Center & Research Institute, physicians travel from the headquarters to its partner hospitals to deliver care and work with doctors at each site. For example, Moffitt leaders are overseeing a program with Memorial Healthcare System in South Florida that focuses on malignant hematology and blood and marrow transplantation, said Louis Harrison, MD, chair for Moffitt’s radiation oncology department and vice president, chief partnership officer.
“These are real partnerships where we put our faculty and our know-how on the ground at these sites,” he said in an interview. “We feel like the only way to deliver care that is representative to Moffitt is to have Moffitt doctors deliver the care.”
The University of Texas MD Anderson Cancer Center, Houston, meanwhile, boasts a robust network of partner members, certified member hospitals, associate members, and affiliates. Partner members are U.S.-based relationships where member health systems integrate their clinical cancer care operations with MD Anderson, said Michael Kupferman, MD, senior vice president of clinical and academic network development at MD Anderson. Certified members receive assessments by MD Anderson and tailored recommendations for clinical quality improvements, while associate members stem from international clinical relationships with MD Anderson. Affiliates have a relationship with MD Anderson in one specialty- or modality-focused area, such as radiation oncology.
“All MD Anderson Cancer Network members operate independently from MD Anderson Cancer Center,” Dr. Kupferman said in an interview. “All cancer network members have access to our expertise and clinical knowledge to improve the level of cancer care in their communities.”
In terms of marketing the different types of network members, Dr. Kupferman said that MD Anderson collaborates with members on internal and external marketing and communications strategies to offer “best practices and guidance on how to best educate the alignment and benefits of the relationship to internal staff and local communities.”
Dr. Kupferman declined to directly comment on how surgical safety at MD Anderson’s member institutions is addressed or respond to the JAMA study findings. “We believe that our cancer network members strive to practice at a level higher than the national safety average, as evidenced by the consistent quality reviews we conduct with our members.”
An opportunity to improve
A key advantage to affiliate cancer centers is the expanded care access they can provide to patients, said Dr. Lichtenfeld. While some patients can bypass their community hospital and travel to a top-ranked cancer hospital for treatment, others do not have that capability.
“Some people will not leave their communities,” he said. “It would be wrong to take this research and point at bad doctors for not sending their patient [to a more specialized hospital]. Sometimes, its patients themselves, by choice or necessity, who can’t go somewhere else.”
Dr. Boffa emphasized that the recent research on safety presents an exciting opportunity for flagship institutions and their affiliates to analyze their structure and make improvements where necessary.
“The fact that [the hospitals] are already connected in some way is a huge advance; that’s half the battle,” Dr. Boffa said. “The next step is how do we distill what elements of care are transferable. How do we leverage this connection to share what makes the safer hospitals safer?”
Risk model could help predict VTE in acute leukemia
AMSTERDAM – A new clinical prediction model can determine the risk of venous thromboembolism in patients with leukemia, according to investigators.
The scoring system, which incorporates historical, morphological, and cytologic factors, was internally validated at multiple time points over the course of a year, reported lead author, Alejandro Lazo-Langner, MD, of the University of Western Ontario, London.
“It is important that we can predict or anticipate which patients [with acute leukemia] will develop venous thrombosis so that we can develop preventions and aim for better surveillance strategies,” Dr. Lazo-Langner said at the annual congress of the European Hematology Association. Venous thromboembolism (VTE) risk modeling is available for patients with solid tumors, but a similar prognostic tool for leukemia patients has been missing.
To fill this practice gap, Dr. Lazo-Langner and colleagues conducted a retrospective cohort study involving 501 patients with acute leukemia who were diagnosed between 2006 and 2017. Of these patients, 427 (85.2%) had myeloid lineage and 74 (14.8%) had lymphoblastic disease. VTE outcomes of interest included proximal lower- and upper-extremity deep vein thrombosis; pulmonary embolism; and thrombosis of unusual sites, such as splanchnic and cerebral. Patients were followed until last follow-up, VTE, or death. Single variable and multiple variable logistic regression were used sequentially to evaluate and confirm potential predictive factors, with nonparametric bootstrapping for internal validation.
After last follow-up, 77 patients (15.3%) had developed VTE; specifically, 44 patients had upper-extremity deep vein thrombosis, 28 had lower-extremity deep vein thrombosis or pulmonary embolism, and 5 had cerebral vein thrombosis. The median time from leukemia diagnosis to VTE was approximately 2 months (64 days). Out of 20 possible predictive factors, 7 were included in the multivariable model, and 3 constitute the final model. These three factors are platelet count greater than 50 x 109/L at time of diagnosis (1 point), lymphoblastic leukemia (2 points), and previous history of venous thromboembolism (3 points).
Dr. Lazo-Langner explained that leukemia patients at high risk of VTE are those with a score of 3 or more points. Using this risk threshold, the investigators found that the overall cumulative incidence of VTE in the high-risk group was 44.0%, compared with 10.5% in the low-risk group. Temporal analysis showed a widening disparity between the two groups, from 3 months (28.8% vs. 6.3%), to 6 months (41.1% vs. 7.9%), and 12 months (42.5% vs. 9.3%).
When asked if treatment type was evaluated, Dr. Lazo-Langner said that treatment type was evaluated but proved unfruitful for the model, which is designed for universal use in leukemia.
“We did include a number of different chemotherapy regimens,” he said. “The problem is, because we included both AML [acute myeloid leukemia] and ALL [acute lymphoblastic leukemia] lineage, and the cornerstone of treatment is different for both lineages. It’s difficult to actually include what kind of chemotherapy [patients had]. For instance, it is known that anthracyclines increase risk of thrombosis, but in both lineages, you use anthracyclines, so you really cannot use that as a predictor.”
Looking to the future, the next step will be validation in other cohorts. If this is successful, then Dr. Lazo-Langner speculated that clinicians could use the scoring system to direct monitoring and treatment. For example, patients with high scores and low platelet counts could receive earlier transfusional support, while all high-risk patients could be placed under more intensive surveillance and given additional education about thrombosis.
“I think recognizing symptoms early is important,” Dr. Lazo-Langner said, “and that would be training not only clinicians, but also nursing personnel and the patients themselves to be aware of the symptoms, so they can actually recognize them sooner.”
The study was funded by the Canadian Institutes of Health Research. Dr. Lazo-Langner is an investigator with the Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network.
SOURCE: Lazo-Langner A et al. EHA 2019, Abstract S1642.
AMSTERDAM – A new clinical prediction model can determine the risk of venous thromboembolism in patients with leukemia, according to investigators.
The scoring system, which incorporates historical, morphological, and cytologic factors, was internally validated at multiple time points over the course of a year, reported lead author, Alejandro Lazo-Langner, MD, of the University of Western Ontario, London.
“It is important that we can predict or anticipate which patients [with acute leukemia] will develop venous thrombosis so that we can develop preventions and aim for better surveillance strategies,” Dr. Lazo-Langner said at the annual congress of the European Hematology Association. Venous thromboembolism (VTE) risk modeling is available for patients with solid tumors, but a similar prognostic tool for leukemia patients has been missing.
To fill this practice gap, Dr. Lazo-Langner and colleagues conducted a retrospective cohort study involving 501 patients with acute leukemia who were diagnosed between 2006 and 2017. Of these patients, 427 (85.2%) had myeloid lineage and 74 (14.8%) had lymphoblastic disease. VTE outcomes of interest included proximal lower- and upper-extremity deep vein thrombosis; pulmonary embolism; and thrombosis of unusual sites, such as splanchnic and cerebral. Patients were followed until last follow-up, VTE, or death. Single variable and multiple variable logistic regression were used sequentially to evaluate and confirm potential predictive factors, with nonparametric bootstrapping for internal validation.
After last follow-up, 77 patients (15.3%) had developed VTE; specifically, 44 patients had upper-extremity deep vein thrombosis, 28 had lower-extremity deep vein thrombosis or pulmonary embolism, and 5 had cerebral vein thrombosis. The median time from leukemia diagnosis to VTE was approximately 2 months (64 days). Out of 20 possible predictive factors, 7 were included in the multivariable model, and 3 constitute the final model. These three factors are platelet count greater than 50 x 109/L at time of diagnosis (1 point), lymphoblastic leukemia (2 points), and previous history of venous thromboembolism (3 points).
Dr. Lazo-Langner explained that leukemia patients at high risk of VTE are those with a score of 3 or more points. Using this risk threshold, the investigators found that the overall cumulative incidence of VTE in the high-risk group was 44.0%, compared with 10.5% in the low-risk group. Temporal analysis showed a widening disparity between the two groups, from 3 months (28.8% vs. 6.3%), to 6 months (41.1% vs. 7.9%), and 12 months (42.5% vs. 9.3%).
When asked if treatment type was evaluated, Dr. Lazo-Langner said that treatment type was evaluated but proved unfruitful for the model, which is designed for universal use in leukemia.
“We did include a number of different chemotherapy regimens,” he said. “The problem is, because we included both AML [acute myeloid leukemia] and ALL [acute lymphoblastic leukemia] lineage, and the cornerstone of treatment is different for both lineages. It’s difficult to actually include what kind of chemotherapy [patients had]. For instance, it is known that anthracyclines increase risk of thrombosis, but in both lineages, you use anthracyclines, so you really cannot use that as a predictor.”
Looking to the future, the next step will be validation in other cohorts. If this is successful, then Dr. Lazo-Langner speculated that clinicians could use the scoring system to direct monitoring and treatment. For example, patients with high scores and low platelet counts could receive earlier transfusional support, while all high-risk patients could be placed under more intensive surveillance and given additional education about thrombosis.
“I think recognizing symptoms early is important,” Dr. Lazo-Langner said, “and that would be training not only clinicians, but also nursing personnel and the patients themselves to be aware of the symptoms, so they can actually recognize them sooner.”
The study was funded by the Canadian Institutes of Health Research. Dr. Lazo-Langner is an investigator with the Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network.
SOURCE: Lazo-Langner A et al. EHA 2019, Abstract S1642.
AMSTERDAM – A new clinical prediction model can determine the risk of venous thromboembolism in patients with leukemia, according to investigators.
The scoring system, which incorporates historical, morphological, and cytologic factors, was internally validated at multiple time points over the course of a year, reported lead author, Alejandro Lazo-Langner, MD, of the University of Western Ontario, London.
“It is important that we can predict or anticipate which patients [with acute leukemia] will develop venous thrombosis so that we can develop preventions and aim for better surveillance strategies,” Dr. Lazo-Langner said at the annual congress of the European Hematology Association. Venous thromboembolism (VTE) risk modeling is available for patients with solid tumors, but a similar prognostic tool for leukemia patients has been missing.
To fill this practice gap, Dr. Lazo-Langner and colleagues conducted a retrospective cohort study involving 501 patients with acute leukemia who were diagnosed between 2006 and 2017. Of these patients, 427 (85.2%) had myeloid lineage and 74 (14.8%) had lymphoblastic disease. VTE outcomes of interest included proximal lower- and upper-extremity deep vein thrombosis; pulmonary embolism; and thrombosis of unusual sites, such as splanchnic and cerebral. Patients were followed until last follow-up, VTE, or death. Single variable and multiple variable logistic regression were used sequentially to evaluate and confirm potential predictive factors, with nonparametric bootstrapping for internal validation.
After last follow-up, 77 patients (15.3%) had developed VTE; specifically, 44 patients had upper-extremity deep vein thrombosis, 28 had lower-extremity deep vein thrombosis or pulmonary embolism, and 5 had cerebral vein thrombosis. The median time from leukemia diagnosis to VTE was approximately 2 months (64 days). Out of 20 possible predictive factors, 7 were included in the multivariable model, and 3 constitute the final model. These three factors are platelet count greater than 50 x 109/L at time of diagnosis (1 point), lymphoblastic leukemia (2 points), and previous history of venous thromboembolism (3 points).
Dr. Lazo-Langner explained that leukemia patients at high risk of VTE are those with a score of 3 or more points. Using this risk threshold, the investigators found that the overall cumulative incidence of VTE in the high-risk group was 44.0%, compared with 10.5% in the low-risk group. Temporal analysis showed a widening disparity between the two groups, from 3 months (28.8% vs. 6.3%), to 6 months (41.1% vs. 7.9%), and 12 months (42.5% vs. 9.3%).
When asked if treatment type was evaluated, Dr. Lazo-Langner said that treatment type was evaluated but proved unfruitful for the model, which is designed for universal use in leukemia.
“We did include a number of different chemotherapy regimens,” he said. “The problem is, because we included both AML [acute myeloid leukemia] and ALL [acute lymphoblastic leukemia] lineage, and the cornerstone of treatment is different for both lineages. It’s difficult to actually include what kind of chemotherapy [patients had]. For instance, it is known that anthracyclines increase risk of thrombosis, but in both lineages, you use anthracyclines, so you really cannot use that as a predictor.”
Looking to the future, the next step will be validation in other cohorts. If this is successful, then Dr. Lazo-Langner speculated that clinicians could use the scoring system to direct monitoring and treatment. For example, patients with high scores and low platelet counts could receive earlier transfusional support, while all high-risk patients could be placed under more intensive surveillance and given additional education about thrombosis.
“I think recognizing symptoms early is important,” Dr. Lazo-Langner said, “and that would be training not only clinicians, but also nursing personnel and the patients themselves to be aware of the symptoms, so they can actually recognize them sooner.”
The study was funded by the Canadian Institutes of Health Research. Dr. Lazo-Langner is an investigator with the Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network.
SOURCE: Lazo-Langner A et al. EHA 2019, Abstract S1642.
REPORTING FROM EHA CONGRESS
Cell count ratios appear to predict thromboembolism in lymphoma
AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.
A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.
“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.
To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.
The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).
Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.
A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).
“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”
Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.
The investigators reported no disclosures.
SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.
AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.
A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.
“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.
To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.
The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).
Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.
A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).
“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”
Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.
The investigators reported no disclosures.
SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.
AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.
A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.
“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.
To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.
The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).
Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.
A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).
“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”
Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.
The investigators reported no disclosures.
SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.
REPORTING FROM EHA CONGRESS
CVD risk upped in postmenopausal breast cancer survivors
according to a new study of nearly 300 women.
Previous studies have shown that cardiovascular risk is greater among postmenopausal women treated for breast cancer compared with those without cancer, but specific risk factors have not been well studied, wrote Daniel de Araujo Brito Buttros, MD, of Paulista State University, Sao Paulo, Brazil, and colleagues.
In a study published in Menopause, the researchers evaluated several CVD risk factors in 96 postmenopausal women with breast cancer and 192 women without breast cancer, including metabolic syndrome, subclinical atherosclerosis, and heat shock proteins (HSP) 60 and 70.
Overall, breast cancer patients had significantly higher HSP60 levels and lower HSP70 levels than those of their cancer-free peers. These two proteins have an antagonistic relationship in cardiovascular disease, with HSP60 considered a risk factor for CVD, and HSP70 considered a protective factor. Average HSP60 levels for the breast cancer and control groups were 35 ng/mL and 10.8 ng/mL, respectively; average HSP70 levels were 0.5 ng/mL and 1.3 ng/mL, respectively.
Both diabetes and metabolic syndrome were significantly more common among breast cancer patients vs. controls (19.8% vs. 6.8% and 54.2% vs. 30.7%, respectively). Carotid artery plaque also was more common in breast cancer patients vs. controls (19.8% vs. 9.4%, respectively, P = 0.013).
In addition, systolic and diastolic blood pressure levels were significantly higher among the breast cancer patients, as were triglycerides and glucose.
The findings were limited by several factors including the cross-sectional design that could not prove a causal relationship between CVD risk and breast cancer, the researchers noted.
However, the results demonstrate the increased CVD risk for breast cancer patients, and “[therefore], women diagnosed with breast cancer might receive multidisciplinary care, including cardiology consultation at the time of breast cancer diagnosis and also during oncologic follow-up visits,” they said.
“Heart disease appears more commonly in women treated for breast cancer because of the toxicities of chemotherapy, radiation therapy, and use of aromatase inhibitors, which lower estrogen. Heart-healthy lifestyle modifications will decrease both the risk of recurrent breast cancer and the risk of developing heart disease,” JoAnn Pinkerton, MD, executive director of the North American Menopause Society, said in a statement. “Women should schedule a cardiology consultation when breast cancer is diagnosed and continue with ongoing follow-up after cancer treatments are completed,” she emphasized.
The researchers had no financial conflicts to disclose.
SOURCE: Buttros DAB et al. Menopause. 2019. doi: 10.1097/GME.0000000000001348.
according to a new study of nearly 300 women.
Previous studies have shown that cardiovascular risk is greater among postmenopausal women treated for breast cancer compared with those without cancer, but specific risk factors have not been well studied, wrote Daniel de Araujo Brito Buttros, MD, of Paulista State University, Sao Paulo, Brazil, and colleagues.
In a study published in Menopause, the researchers evaluated several CVD risk factors in 96 postmenopausal women with breast cancer and 192 women without breast cancer, including metabolic syndrome, subclinical atherosclerosis, and heat shock proteins (HSP) 60 and 70.
Overall, breast cancer patients had significantly higher HSP60 levels and lower HSP70 levels than those of their cancer-free peers. These two proteins have an antagonistic relationship in cardiovascular disease, with HSP60 considered a risk factor for CVD, and HSP70 considered a protective factor. Average HSP60 levels for the breast cancer and control groups were 35 ng/mL and 10.8 ng/mL, respectively; average HSP70 levels were 0.5 ng/mL and 1.3 ng/mL, respectively.
Both diabetes and metabolic syndrome were significantly more common among breast cancer patients vs. controls (19.8% vs. 6.8% and 54.2% vs. 30.7%, respectively). Carotid artery plaque also was more common in breast cancer patients vs. controls (19.8% vs. 9.4%, respectively, P = 0.013).
In addition, systolic and diastolic blood pressure levels were significantly higher among the breast cancer patients, as were triglycerides and glucose.
The findings were limited by several factors including the cross-sectional design that could not prove a causal relationship between CVD risk and breast cancer, the researchers noted.
However, the results demonstrate the increased CVD risk for breast cancer patients, and “[therefore], women diagnosed with breast cancer might receive multidisciplinary care, including cardiology consultation at the time of breast cancer diagnosis and also during oncologic follow-up visits,” they said.
“Heart disease appears more commonly in women treated for breast cancer because of the toxicities of chemotherapy, radiation therapy, and use of aromatase inhibitors, which lower estrogen. Heart-healthy lifestyle modifications will decrease both the risk of recurrent breast cancer and the risk of developing heart disease,” JoAnn Pinkerton, MD, executive director of the North American Menopause Society, said in a statement. “Women should schedule a cardiology consultation when breast cancer is diagnosed and continue with ongoing follow-up after cancer treatments are completed,” she emphasized.
The researchers had no financial conflicts to disclose.
SOURCE: Buttros DAB et al. Menopause. 2019. doi: 10.1097/GME.0000000000001348.
according to a new study of nearly 300 women.
Previous studies have shown that cardiovascular risk is greater among postmenopausal women treated for breast cancer compared with those without cancer, but specific risk factors have not been well studied, wrote Daniel de Araujo Brito Buttros, MD, of Paulista State University, Sao Paulo, Brazil, and colleagues.
In a study published in Menopause, the researchers evaluated several CVD risk factors in 96 postmenopausal women with breast cancer and 192 women without breast cancer, including metabolic syndrome, subclinical atherosclerosis, and heat shock proteins (HSP) 60 and 70.
Overall, breast cancer patients had significantly higher HSP60 levels and lower HSP70 levels than those of their cancer-free peers. These two proteins have an antagonistic relationship in cardiovascular disease, with HSP60 considered a risk factor for CVD, and HSP70 considered a protective factor. Average HSP60 levels for the breast cancer and control groups were 35 ng/mL and 10.8 ng/mL, respectively; average HSP70 levels were 0.5 ng/mL and 1.3 ng/mL, respectively.
Both diabetes and metabolic syndrome were significantly more common among breast cancer patients vs. controls (19.8% vs. 6.8% and 54.2% vs. 30.7%, respectively). Carotid artery plaque also was more common in breast cancer patients vs. controls (19.8% vs. 9.4%, respectively, P = 0.013).
In addition, systolic and diastolic blood pressure levels were significantly higher among the breast cancer patients, as were triglycerides and glucose.
The findings were limited by several factors including the cross-sectional design that could not prove a causal relationship between CVD risk and breast cancer, the researchers noted.
However, the results demonstrate the increased CVD risk for breast cancer patients, and “[therefore], women diagnosed with breast cancer might receive multidisciplinary care, including cardiology consultation at the time of breast cancer diagnosis and also during oncologic follow-up visits,” they said.
“Heart disease appears more commonly in women treated for breast cancer because of the toxicities of chemotherapy, radiation therapy, and use of aromatase inhibitors, which lower estrogen. Heart-healthy lifestyle modifications will decrease both the risk of recurrent breast cancer and the risk of developing heart disease,” JoAnn Pinkerton, MD, executive director of the North American Menopause Society, said in a statement. “Women should schedule a cardiology consultation when breast cancer is diagnosed and continue with ongoing follow-up after cancer treatments are completed,” she emphasized.
The researchers had no financial conflicts to disclose.
SOURCE: Buttros DAB et al. Menopause. 2019. doi: 10.1097/GME.0000000000001348.
FROM MENOPAUSE
Immunotherapy-treated NSCLC: Adverse impact of steroids driven by palliative indications
Giving steroids for indications other than cancer palliation doesn’t compromise the effectiveness of immunotherapy for advanced non–small cell lung cancer (NSCLC), suggests a single-center retrospective cohort study.
The immunosuppressant activity of corticosteroids and recent reports linking them to poorer outcomes has raised concern about their use during immunotherapy, noted Biagio Ricciuti, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. But mechanisms underpinning this association are unclear.
The investigators studied 650 patients with NSCLC treated with immunotherapy targeting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), either as monotherapy or with other immunotherapy. Overall, 14.3% were receiving 10 mg or more of prednisone daily when they started the immunotherapy, a cutoff selected for study because it has been used an exclusion criterion for clinical trials.
Results reported in the Journal of Clinical Oncology showed that, compared with other patients, those who received 10 mg or more of steroids indeed had poorer median progression-free survival (2.0 vs. 3.4 months; P = .01) and overall survival (4.9 vs. 11.2 months; P less than .001).
However, when the indication for steroid therapy was considered, median progression-free survival was just 1.4 months among patients who received 10 mg or more prednisone for cancer-related palliation, compared with 4.6 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons (for example, autoimmune disease, chronic obstructive pulmonary disease flare, hypersensitivity prophylaxis, or management of noncancer pain) and 3.4 months among patients who received 0-10 mg of prednisone (P less than .001 across groups).
Similarly, median overall survival was just 2.2 months among patients who received 10 mg or more prednisone for palliative indications, but 10.7 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons and 11.2 months among patients who received less than 10 mg prednisone (P less than .001 across groups).
In a multivariate analysis that adjusted for performance status and PD-L1 positivity and that used patients receiving up to 10 mg prednisone as the comparator, patients receiving 10 mg or more for cancer palliation had a trend toward high risk of progression-free survival events and a higher risk of death (hazard ratio, 1.40; P less than .06 and HR, 1.60; P = .02, respectively). In contrast, patients receiving 10 mg or more for cancer-unrelated reasons did not have elevated risks (HR, 0.62; P = .14 and HR, 0.91; P = .79, respectively).
“These data suggest that the significantly worse outcomes among patients who receive corticosteroids before immunotherapy are driven by the group of patients treated with corticosteroids for palliative oncologic symptom management, rather than by patients receiving corticosteroids for other reasons,” Dr. Ricciuti and coinvestigators wrote. “Corticosteroid use for cancer symptom management might simply correlate with patients who have adverse prognostic factors (e.g., brain metastases and poor performance status) rather than cause a clinically significant blunting of the response to [immune checkpoint inhibitors].
“Our data suggest that corticosteroids should not necessarily be decreased or discontinued before the start of immunotherapy out of a theoretical concern that corticosteroids could impair a response to immunotherapy,” the investigators concluded. “Additional mechanistic studies are needed to identify whether the use of corticosteroids affects specific aspects of the immune system necessary for immunotherapy activity.”
Dr. Ricciuti reported that he has no relevant conflicts of interest. The study did not receive any funding.
SOURCE: Ricciuti B et al. J Clin Oncol. 2019 Jun 17. doi: 10.1200/JCO.19.00189.
Giving steroids for indications other than cancer palliation doesn’t compromise the effectiveness of immunotherapy for advanced non–small cell lung cancer (NSCLC), suggests a single-center retrospective cohort study.
The immunosuppressant activity of corticosteroids and recent reports linking them to poorer outcomes has raised concern about their use during immunotherapy, noted Biagio Ricciuti, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. But mechanisms underpinning this association are unclear.
The investigators studied 650 patients with NSCLC treated with immunotherapy targeting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), either as monotherapy or with other immunotherapy. Overall, 14.3% were receiving 10 mg or more of prednisone daily when they started the immunotherapy, a cutoff selected for study because it has been used an exclusion criterion for clinical trials.
Results reported in the Journal of Clinical Oncology showed that, compared with other patients, those who received 10 mg or more of steroids indeed had poorer median progression-free survival (2.0 vs. 3.4 months; P = .01) and overall survival (4.9 vs. 11.2 months; P less than .001).
However, when the indication for steroid therapy was considered, median progression-free survival was just 1.4 months among patients who received 10 mg or more prednisone for cancer-related palliation, compared with 4.6 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons (for example, autoimmune disease, chronic obstructive pulmonary disease flare, hypersensitivity prophylaxis, or management of noncancer pain) and 3.4 months among patients who received 0-10 mg of prednisone (P less than .001 across groups).
Similarly, median overall survival was just 2.2 months among patients who received 10 mg or more prednisone for palliative indications, but 10.7 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons and 11.2 months among patients who received less than 10 mg prednisone (P less than .001 across groups).
In a multivariate analysis that adjusted for performance status and PD-L1 positivity and that used patients receiving up to 10 mg prednisone as the comparator, patients receiving 10 mg or more for cancer palliation had a trend toward high risk of progression-free survival events and a higher risk of death (hazard ratio, 1.40; P less than .06 and HR, 1.60; P = .02, respectively). In contrast, patients receiving 10 mg or more for cancer-unrelated reasons did not have elevated risks (HR, 0.62; P = .14 and HR, 0.91; P = .79, respectively).
“These data suggest that the significantly worse outcomes among patients who receive corticosteroids before immunotherapy are driven by the group of patients treated with corticosteroids for palliative oncologic symptom management, rather than by patients receiving corticosteroids for other reasons,” Dr. Ricciuti and coinvestigators wrote. “Corticosteroid use for cancer symptom management might simply correlate with patients who have adverse prognostic factors (e.g., brain metastases and poor performance status) rather than cause a clinically significant blunting of the response to [immune checkpoint inhibitors].
“Our data suggest that corticosteroids should not necessarily be decreased or discontinued before the start of immunotherapy out of a theoretical concern that corticosteroids could impair a response to immunotherapy,” the investigators concluded. “Additional mechanistic studies are needed to identify whether the use of corticosteroids affects specific aspects of the immune system necessary for immunotherapy activity.”
Dr. Ricciuti reported that he has no relevant conflicts of interest. The study did not receive any funding.
SOURCE: Ricciuti B et al. J Clin Oncol. 2019 Jun 17. doi: 10.1200/JCO.19.00189.
Giving steroids for indications other than cancer palliation doesn’t compromise the effectiveness of immunotherapy for advanced non–small cell lung cancer (NSCLC), suggests a single-center retrospective cohort study.
The immunosuppressant activity of corticosteroids and recent reports linking them to poorer outcomes has raised concern about their use during immunotherapy, noted Biagio Ricciuti, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. But mechanisms underpinning this association are unclear.
The investigators studied 650 patients with NSCLC treated with immunotherapy targeting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), either as monotherapy or with other immunotherapy. Overall, 14.3% were receiving 10 mg or more of prednisone daily when they started the immunotherapy, a cutoff selected for study because it has been used an exclusion criterion for clinical trials.
Results reported in the Journal of Clinical Oncology showed that, compared with other patients, those who received 10 mg or more of steroids indeed had poorer median progression-free survival (2.0 vs. 3.4 months; P = .01) and overall survival (4.9 vs. 11.2 months; P less than .001).
However, when the indication for steroid therapy was considered, median progression-free survival was just 1.4 months among patients who received 10 mg or more prednisone for cancer-related palliation, compared with 4.6 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons (for example, autoimmune disease, chronic obstructive pulmonary disease flare, hypersensitivity prophylaxis, or management of noncancer pain) and 3.4 months among patients who received 0-10 mg of prednisone (P less than .001 across groups).
Similarly, median overall survival was just 2.2 months among patients who received 10 mg or more prednisone for palliative indications, but 10.7 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons and 11.2 months among patients who received less than 10 mg prednisone (P less than .001 across groups).
In a multivariate analysis that adjusted for performance status and PD-L1 positivity and that used patients receiving up to 10 mg prednisone as the comparator, patients receiving 10 mg or more for cancer palliation had a trend toward high risk of progression-free survival events and a higher risk of death (hazard ratio, 1.40; P less than .06 and HR, 1.60; P = .02, respectively). In contrast, patients receiving 10 mg or more for cancer-unrelated reasons did not have elevated risks (HR, 0.62; P = .14 and HR, 0.91; P = .79, respectively).
“These data suggest that the significantly worse outcomes among patients who receive corticosteroids before immunotherapy are driven by the group of patients treated with corticosteroids for palliative oncologic symptom management, rather than by patients receiving corticosteroids for other reasons,” Dr. Ricciuti and coinvestigators wrote. “Corticosteroid use for cancer symptom management might simply correlate with patients who have adverse prognostic factors (e.g., brain metastases and poor performance status) rather than cause a clinically significant blunting of the response to [immune checkpoint inhibitors].
“Our data suggest that corticosteroids should not necessarily be decreased or discontinued before the start of immunotherapy out of a theoretical concern that corticosteroids could impair a response to immunotherapy,” the investigators concluded. “Additional mechanistic studies are needed to identify whether the use of corticosteroids affects specific aspects of the immune system necessary for immunotherapy activity.”
Dr. Ricciuti reported that he has no relevant conflicts of interest. The study did not receive any funding.
SOURCE: Ricciuti B et al. J Clin Oncol. 2019 Jun 17. doi: 10.1200/JCO.19.00189.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Checkpoint inhibitor–induced rheumatic complications have unique features
MADRID – The musculoskeletal complications of checkpoint inhibitors therapy are sometimes described as RA like, but a detailed analysis of a consecutive series of patients presented at the European Congress of Rheumatology produced the conclusion that the phenotypic expression is unique.
“These manifestations do not necessarily include synovial involvement, so their description as a rheumatoid arthritis–like presentation is not accurate. Rather, our findings suggest the pathology is something completely different and completely new,” said Alexandra Filippopoulou, MD, a rheumatology resident at the University of Patras (Greece).
This comment was based on a prospective study evaluating musculoskeletal complications in patients treated with checkpoint inhibitors over a recent 2-year period. Of the 130 consecutive patients who received a checkpoint inhibitor in the study period, 10 (7.7%) complained of joint pain and were determined to have an inflammatory complication.
The median time to development of musculoskeletal symptoms in this mostly male patient series was 2.5 months. The site of cancer was lung in four, bladder in three, kidney in two, and skin in one. Nivolumab (Opdivo) was the most common checkpoint inhibitor used, but others were represented.
MRI studies were conducted in 8 of the 10 patients. Overall, the MRI studies showed more myofascial than synovial involvement, but Dr. Filippopoulou described three distinct patterns.
In four patients, there was prominent periarticular involvement marked by diffuse swelling in the hands, feet, knees, or a combination of these joints. Synovitis, when observed, was mild, but myositis and fasciitis were common in adjacent tissues.
In three patients with a chief complaint of knee pain, myofasciitis was prominent in the surrounding muscles. Again, synovitis, when observed, was mild. It was unclear whether a partial tear of the quadriceps tendon observed in one patient was checkpoint inhibitor related.
In a third pattern, shared by three other patients, synovitis was prominent, but so was myositis in adjacent muscles. In two of these patients, the inflammatory activity was confined to the hands; in the third, both the knees and the ankle were also involved.
Regardless of these patterns of inflammation, “almost all of these patients continued to show good range of motion, which is not something that is commonly seen in patients with rheumatoid arthritis,” Dr. Filippopoulou observed.
Overall, the joint pain tended to be mild to moderate. They all responded well to low-dose glucocorticoids or analgesics without need to discontinue the anticancer therapy, Dr. Filippopoulou reported.
Not least interesting of the findings, 50% of the patients with musculoskeletal adverse events had a favorable response to the checkpoint inhibitor therapy, compared with just 12.5% of patients without these complaints, a difference that reached statistical significance (P = .0016), according to Dr. Filippopoulou. This observation is consistent with a study published last year that also associated immune-related adverse events with a greater likelihood of an anticancer response (Ann Rheumatic Dis. 2018;77:393-8).
“This is an interesting finding, but the theory that musculoskeletal adverse events predict a better response to checkpoint inhibitor therapy needs to be proven,” she said.
A larger case series is needed to better characterize joint inflammation associated with checkpoint inhibitors, but Dr. Filippopoulou concluded from her series that these adverse events are not accurately described as RA like. Rather, the phenotypic expression appears to be unique, not fully resembling any other joint pathology.
Dr. Filippopoulou reported no potential conflicts of interest.
SOURCE: Filippopoulou A et al. Ann Rheum Dis. Jun 2019;78 (Suppl 2):251. Abstract OP0335. doi: 10.1136/annrheumdis-2019-eular.5029.
MADRID – The musculoskeletal complications of checkpoint inhibitors therapy are sometimes described as RA like, but a detailed analysis of a consecutive series of patients presented at the European Congress of Rheumatology produced the conclusion that the phenotypic expression is unique.
“These manifestations do not necessarily include synovial involvement, so their description as a rheumatoid arthritis–like presentation is not accurate. Rather, our findings suggest the pathology is something completely different and completely new,” said Alexandra Filippopoulou, MD, a rheumatology resident at the University of Patras (Greece).
This comment was based on a prospective study evaluating musculoskeletal complications in patients treated with checkpoint inhibitors over a recent 2-year period. Of the 130 consecutive patients who received a checkpoint inhibitor in the study period, 10 (7.7%) complained of joint pain and were determined to have an inflammatory complication.
The median time to development of musculoskeletal symptoms in this mostly male patient series was 2.5 months. The site of cancer was lung in four, bladder in three, kidney in two, and skin in one. Nivolumab (Opdivo) was the most common checkpoint inhibitor used, but others were represented.
MRI studies were conducted in 8 of the 10 patients. Overall, the MRI studies showed more myofascial than synovial involvement, but Dr. Filippopoulou described three distinct patterns.
In four patients, there was prominent periarticular involvement marked by diffuse swelling in the hands, feet, knees, or a combination of these joints. Synovitis, when observed, was mild, but myositis and fasciitis were common in adjacent tissues.
In three patients with a chief complaint of knee pain, myofasciitis was prominent in the surrounding muscles. Again, synovitis, when observed, was mild. It was unclear whether a partial tear of the quadriceps tendon observed in one patient was checkpoint inhibitor related.
In a third pattern, shared by three other patients, synovitis was prominent, but so was myositis in adjacent muscles. In two of these patients, the inflammatory activity was confined to the hands; in the third, both the knees and the ankle were also involved.
Regardless of these patterns of inflammation, “almost all of these patients continued to show good range of motion, which is not something that is commonly seen in patients with rheumatoid arthritis,” Dr. Filippopoulou observed.
Overall, the joint pain tended to be mild to moderate. They all responded well to low-dose glucocorticoids or analgesics without need to discontinue the anticancer therapy, Dr. Filippopoulou reported.
Not least interesting of the findings, 50% of the patients with musculoskeletal adverse events had a favorable response to the checkpoint inhibitor therapy, compared with just 12.5% of patients without these complaints, a difference that reached statistical significance (P = .0016), according to Dr. Filippopoulou. This observation is consistent with a study published last year that also associated immune-related adverse events with a greater likelihood of an anticancer response (Ann Rheumatic Dis. 2018;77:393-8).
“This is an interesting finding, but the theory that musculoskeletal adverse events predict a better response to checkpoint inhibitor therapy needs to be proven,” she said.
A larger case series is needed to better characterize joint inflammation associated with checkpoint inhibitors, but Dr. Filippopoulou concluded from her series that these adverse events are not accurately described as RA like. Rather, the phenotypic expression appears to be unique, not fully resembling any other joint pathology.
Dr. Filippopoulou reported no potential conflicts of interest.
SOURCE: Filippopoulou A et al. Ann Rheum Dis. Jun 2019;78 (Suppl 2):251. Abstract OP0335. doi: 10.1136/annrheumdis-2019-eular.5029.
MADRID – The musculoskeletal complications of checkpoint inhibitors therapy are sometimes described as RA like, but a detailed analysis of a consecutive series of patients presented at the European Congress of Rheumatology produced the conclusion that the phenotypic expression is unique.
“These manifestations do not necessarily include synovial involvement, so their description as a rheumatoid arthritis–like presentation is not accurate. Rather, our findings suggest the pathology is something completely different and completely new,” said Alexandra Filippopoulou, MD, a rheumatology resident at the University of Patras (Greece).
This comment was based on a prospective study evaluating musculoskeletal complications in patients treated with checkpoint inhibitors over a recent 2-year period. Of the 130 consecutive patients who received a checkpoint inhibitor in the study period, 10 (7.7%) complained of joint pain and were determined to have an inflammatory complication.
The median time to development of musculoskeletal symptoms in this mostly male patient series was 2.5 months. The site of cancer was lung in four, bladder in three, kidney in two, and skin in one. Nivolumab (Opdivo) was the most common checkpoint inhibitor used, but others were represented.
MRI studies were conducted in 8 of the 10 patients. Overall, the MRI studies showed more myofascial than synovial involvement, but Dr. Filippopoulou described three distinct patterns.
In four patients, there was prominent periarticular involvement marked by diffuse swelling in the hands, feet, knees, or a combination of these joints. Synovitis, when observed, was mild, but myositis and fasciitis were common in adjacent tissues.
In three patients with a chief complaint of knee pain, myofasciitis was prominent in the surrounding muscles. Again, synovitis, when observed, was mild. It was unclear whether a partial tear of the quadriceps tendon observed in one patient was checkpoint inhibitor related.
In a third pattern, shared by three other patients, synovitis was prominent, but so was myositis in adjacent muscles. In two of these patients, the inflammatory activity was confined to the hands; in the third, both the knees and the ankle were also involved.
Regardless of these patterns of inflammation, “almost all of these patients continued to show good range of motion, which is not something that is commonly seen in patients with rheumatoid arthritis,” Dr. Filippopoulou observed.
Overall, the joint pain tended to be mild to moderate. They all responded well to low-dose glucocorticoids or analgesics without need to discontinue the anticancer therapy, Dr. Filippopoulou reported.
Not least interesting of the findings, 50% of the patients with musculoskeletal adverse events had a favorable response to the checkpoint inhibitor therapy, compared with just 12.5% of patients without these complaints, a difference that reached statistical significance (P = .0016), according to Dr. Filippopoulou. This observation is consistent with a study published last year that also associated immune-related adverse events with a greater likelihood of an anticancer response (Ann Rheumatic Dis. 2018;77:393-8).
“This is an interesting finding, but the theory that musculoskeletal adverse events predict a better response to checkpoint inhibitor therapy needs to be proven,” she said.
A larger case series is needed to better characterize joint inflammation associated with checkpoint inhibitors, but Dr. Filippopoulou concluded from her series that these adverse events are not accurately described as RA like. Rather, the phenotypic expression appears to be unique, not fully resembling any other joint pathology.
Dr. Filippopoulou reported no potential conflicts of interest.
SOURCE: Filippopoulou A et al. Ann Rheum Dis. Jun 2019;78 (Suppl 2):251. Abstract OP0335. doi: 10.1136/annrheumdis-2019-eular.5029.
REPORTING FROM EULAR 2019 CONGRESS
Pregnancy deemed safe in BRCA-mutated breast cancer survivors
CHICAGO – Pregnancy after breast cancer is safe in BRCA-mutated patients, according to a retrospective study.
Pregnancy did not affect disease-free or overall survival in a cohort of BRCA-mutated breast cancer patients. Additionally, fetal and pregnancy complications in this cohort were similar to complications observed in the general population.
“We believe that our findings provide reassurance for counseling young BRCA-mutated breast cancer patients inquiring about the feasibility and safety of future conception,” said Matteo Lambertini, MD, PhD, of Policlinico San Martino Hospital in Genova, Italy.
Dr. Lambertini presented the findings at the annual meeting of the American Society of Clinical Oncology.
He and his colleagues conducted an international, multicenter, retrospective cohort study of 1,252 patients. The patients had been diagnosed with stage I-III breast cancer between January 2000 and December 2012 at age 40 years or younger. All patients had BRCA mutations – 811 with BRCA1 alone, 430 with BRCA2 alone, and 11 with both.
Pregnant versus nonpregnant patients
At a median of 4.5 years after diagnosis, 195 patients (16%) had experienced a pregnancy.
Compared with the nonpregnant women, pregnant patients were younger (P less than .001), more likely to have a BRCA1 mutation (P = .01), have smaller tumors (P = .04), have node-negative disease (P = .003), and have hormone receptor–negative tumors (P = .002). Roughly 95% of patients in both cohorts had received chemotherapy, and the most common regimens were anthracycline or taxane based.
Compared with patients in the nonpregnancy cohort, those in the pregnancy cohort were less likely to receive tamoxifen alone as endocrine therapy (P = .002), were more likely to have a shorter duration of endocrine therapy (P less than .001), and were less likely to undergo salpingo-oophorectomy (P less than .001).
Pregnancy outcomes
“In terms of pregnancy, fetal, and obstetrical outcomes, no alarming signals were observed,” Dr. Lambertini said.
Most pregnant patients had a spontaneous pregnancy (82.1%), completed the pregnancy (76.9%), delivered at term (90.8%), and had no complications (86.6%). However, 10.3% of patients had a spontaneous abortion, 9.2% of pregnancies were pre term, and 1.8% of babies had congenital abnormalities.
“All these rates were highly comparable to rates that are expected in the general healthy population,” Dr. Lambertini said.
Survival analyses
The researchers performed two survival analyses. The first was a case-control approach in which they matched each pregnant patient with three controls (patients without pregnancy) according to the following:
- Disease-free interval from breast cancer diagnosis (equal to or longer than that of pregnant patients).
- Year at diagnosis (plus or minus 2.5 years).
- Nodal status (negative vs. positive).
- Hormone receptor status (positive vs. negative).
- Type of BRCA mutation (BRCA1 vs. BRCA2).
The second survival analysis was an extended Cox model with pregnancy as a time-varying covariate.
Survival outcomes
At a median follow-up of 8.3 years, pregnant patients had better disease-free survival than nonpregnant patients in the case-control analysis, with a hazard ratio of 0.71 (P = .045). With the extended Cox model, the adjusted HR was 0.87 (P = .41). The analysis was adjusted for age, tumor size, nodal status, type of endocrine therapy, hormone receptor status, breast surgery, and BRCA mutation.
There was a significant interaction between type of BRCA mutation and pregnancy, with better disease-free survival observed in the BRCA1-mutated cohort. The HR was 0.53 in the BRCA1 cohort and 1.60 in the BRCA2 cohort (P less than .01). However, as Dr. Lambertini pointed out, only 44 pregnant patients had a BRCA1 mutation.
There was no significant interaction between hormone receptor status and pregnancy (P = .28).
Furthermore, there was no significant difference in overall survival between the pregnant and nonpregnant cohorts. In the case-control analysis, the HR was 0.86 (P = .65). In the extended Cox model, the adjusted HR was 0.88 (P = .66).
Dr. Lambertini disclosed a relationship with Teva.
SOURCE: Lambertini M et al. ASCO 2019, Abstract 11506.
CHICAGO – Pregnancy after breast cancer is safe in BRCA-mutated patients, according to a retrospective study.
Pregnancy did not affect disease-free or overall survival in a cohort of BRCA-mutated breast cancer patients. Additionally, fetal and pregnancy complications in this cohort were similar to complications observed in the general population.
“We believe that our findings provide reassurance for counseling young BRCA-mutated breast cancer patients inquiring about the feasibility and safety of future conception,” said Matteo Lambertini, MD, PhD, of Policlinico San Martino Hospital in Genova, Italy.
Dr. Lambertini presented the findings at the annual meeting of the American Society of Clinical Oncology.
He and his colleagues conducted an international, multicenter, retrospective cohort study of 1,252 patients. The patients had been diagnosed with stage I-III breast cancer between January 2000 and December 2012 at age 40 years or younger. All patients had BRCA mutations – 811 with BRCA1 alone, 430 with BRCA2 alone, and 11 with both.
Pregnant versus nonpregnant patients
At a median of 4.5 years after diagnosis, 195 patients (16%) had experienced a pregnancy.
Compared with the nonpregnant women, pregnant patients were younger (P less than .001), more likely to have a BRCA1 mutation (P = .01), have smaller tumors (P = .04), have node-negative disease (P = .003), and have hormone receptor–negative tumors (P = .002). Roughly 95% of patients in both cohorts had received chemotherapy, and the most common regimens were anthracycline or taxane based.
Compared with patients in the nonpregnancy cohort, those in the pregnancy cohort were less likely to receive tamoxifen alone as endocrine therapy (P = .002), were more likely to have a shorter duration of endocrine therapy (P less than .001), and were less likely to undergo salpingo-oophorectomy (P less than .001).
Pregnancy outcomes
“In terms of pregnancy, fetal, and obstetrical outcomes, no alarming signals were observed,” Dr. Lambertini said.
Most pregnant patients had a spontaneous pregnancy (82.1%), completed the pregnancy (76.9%), delivered at term (90.8%), and had no complications (86.6%). However, 10.3% of patients had a spontaneous abortion, 9.2% of pregnancies were pre term, and 1.8% of babies had congenital abnormalities.
“All these rates were highly comparable to rates that are expected in the general healthy population,” Dr. Lambertini said.
Survival analyses
The researchers performed two survival analyses. The first was a case-control approach in which they matched each pregnant patient with three controls (patients without pregnancy) according to the following:
- Disease-free interval from breast cancer diagnosis (equal to or longer than that of pregnant patients).
- Year at diagnosis (plus or minus 2.5 years).
- Nodal status (negative vs. positive).
- Hormone receptor status (positive vs. negative).
- Type of BRCA mutation (BRCA1 vs. BRCA2).
The second survival analysis was an extended Cox model with pregnancy as a time-varying covariate.
Survival outcomes
At a median follow-up of 8.3 years, pregnant patients had better disease-free survival than nonpregnant patients in the case-control analysis, with a hazard ratio of 0.71 (P = .045). With the extended Cox model, the adjusted HR was 0.87 (P = .41). The analysis was adjusted for age, tumor size, nodal status, type of endocrine therapy, hormone receptor status, breast surgery, and BRCA mutation.
There was a significant interaction between type of BRCA mutation and pregnancy, with better disease-free survival observed in the BRCA1-mutated cohort. The HR was 0.53 in the BRCA1 cohort and 1.60 in the BRCA2 cohort (P less than .01). However, as Dr. Lambertini pointed out, only 44 pregnant patients had a BRCA1 mutation.
There was no significant interaction between hormone receptor status and pregnancy (P = .28).
Furthermore, there was no significant difference in overall survival between the pregnant and nonpregnant cohorts. In the case-control analysis, the HR was 0.86 (P = .65). In the extended Cox model, the adjusted HR was 0.88 (P = .66).
Dr. Lambertini disclosed a relationship with Teva.
SOURCE: Lambertini M et al. ASCO 2019, Abstract 11506.
CHICAGO – Pregnancy after breast cancer is safe in BRCA-mutated patients, according to a retrospective study.
Pregnancy did not affect disease-free or overall survival in a cohort of BRCA-mutated breast cancer patients. Additionally, fetal and pregnancy complications in this cohort were similar to complications observed in the general population.
“We believe that our findings provide reassurance for counseling young BRCA-mutated breast cancer patients inquiring about the feasibility and safety of future conception,” said Matteo Lambertini, MD, PhD, of Policlinico San Martino Hospital in Genova, Italy.
Dr. Lambertini presented the findings at the annual meeting of the American Society of Clinical Oncology.
He and his colleagues conducted an international, multicenter, retrospective cohort study of 1,252 patients. The patients had been diagnosed with stage I-III breast cancer between January 2000 and December 2012 at age 40 years or younger. All patients had BRCA mutations – 811 with BRCA1 alone, 430 with BRCA2 alone, and 11 with both.
Pregnant versus nonpregnant patients
At a median of 4.5 years after diagnosis, 195 patients (16%) had experienced a pregnancy.
Compared with the nonpregnant women, pregnant patients were younger (P less than .001), more likely to have a BRCA1 mutation (P = .01), have smaller tumors (P = .04), have node-negative disease (P = .003), and have hormone receptor–negative tumors (P = .002). Roughly 95% of patients in both cohorts had received chemotherapy, and the most common regimens were anthracycline or taxane based.
Compared with patients in the nonpregnancy cohort, those in the pregnancy cohort were less likely to receive tamoxifen alone as endocrine therapy (P = .002), were more likely to have a shorter duration of endocrine therapy (P less than .001), and were less likely to undergo salpingo-oophorectomy (P less than .001).
Pregnancy outcomes
“In terms of pregnancy, fetal, and obstetrical outcomes, no alarming signals were observed,” Dr. Lambertini said.
Most pregnant patients had a spontaneous pregnancy (82.1%), completed the pregnancy (76.9%), delivered at term (90.8%), and had no complications (86.6%). However, 10.3% of patients had a spontaneous abortion, 9.2% of pregnancies were pre term, and 1.8% of babies had congenital abnormalities.
“All these rates were highly comparable to rates that are expected in the general healthy population,” Dr. Lambertini said.
Survival analyses
The researchers performed two survival analyses. The first was a case-control approach in which they matched each pregnant patient with three controls (patients without pregnancy) according to the following:
- Disease-free interval from breast cancer diagnosis (equal to or longer than that of pregnant patients).
- Year at diagnosis (plus or minus 2.5 years).
- Nodal status (negative vs. positive).
- Hormone receptor status (positive vs. negative).
- Type of BRCA mutation (BRCA1 vs. BRCA2).
The second survival analysis was an extended Cox model with pregnancy as a time-varying covariate.
Survival outcomes
At a median follow-up of 8.3 years, pregnant patients had better disease-free survival than nonpregnant patients in the case-control analysis, with a hazard ratio of 0.71 (P = .045). With the extended Cox model, the adjusted HR was 0.87 (P = .41). The analysis was adjusted for age, tumor size, nodal status, type of endocrine therapy, hormone receptor status, breast surgery, and BRCA mutation.
There was a significant interaction between type of BRCA mutation and pregnancy, with better disease-free survival observed in the BRCA1-mutated cohort. The HR was 0.53 in the BRCA1 cohort and 1.60 in the BRCA2 cohort (P less than .01). However, as Dr. Lambertini pointed out, only 44 pregnant patients had a BRCA1 mutation.
There was no significant interaction between hormone receptor status and pregnancy (P = .28).
Furthermore, there was no significant difference in overall survival between the pregnant and nonpregnant cohorts. In the case-control analysis, the HR was 0.86 (P = .65). In the extended Cox model, the adjusted HR was 0.88 (P = .66).
Dr. Lambertini disclosed a relationship with Teva.
SOURCE: Lambertini M et al. ASCO 2019, Abstract 11506.
REPORTING FROM ASCO 2019
Rituximab serious infection risk predicted by immunoglobulin levels
Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.
In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.
“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.
Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.
“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.
Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.
Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).
One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.
Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.
The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.
Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.
Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.
“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.
In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).
Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.
Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.
“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.
They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.
They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”
The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.
SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.
Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.
In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.
“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.
Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.
“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.
Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.
Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).
One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.
Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.
The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.
Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.
Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.
“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.
In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).
Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.
Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.
“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.
They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.
They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”
The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.
SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.
Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.
In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.
“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.
Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.
“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.
Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.
Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).
One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.
Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.
The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.
Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.
Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.
“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.
In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).
Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.
Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.
“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.
They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.
They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”
The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.
SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point: Immunoglobulin should be monitored at baseline and before each rituximab cycle to identify patients at risk of serious infection events (SIEs).
Major finding: SIE rates per 100 patient-years were 16.4 and 21.3 in patients with low (less than 6 g/L) IgG at baseline and during rituximab cycles versus 9.7 for patients with normal (6–16 g/L) IgG levels.
Study details: A retrospective, single-center, longitudinal study involving 700 rituximab-treated patients with rheumatoid arthritis and other rheumatic and musculoskeletal diseases.
Disclosures: The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in the United Kingdom. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.
Source: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.
Olanzapine improves upon standard antiemetic therapy
CHICAGO – Olanzapine plus aprepitant, palonosetron, and dexamethasone (APD) can be considered a new standard antiemetic therapy for patients receiving cisplatin-based chemotherapy, according to a speaker at the annual meeting of the American Society for Clinical Oncology.
A 5 mg dose of olanzapine plus APD produced significantly higher complete response (CR) rates than APD plus placebo in a phase 3 trial, said Hironobu Hashimoto, BPharm, of the National Cancer Center Hospital in Tokyo.
In addition, olanzapine plus APD had a significantly longer time to treatment failure and produced higher rates of complete control and total control. However, rates of somnolence, dizziness, and dry mouth were significantly higher with olanzapine plus APD.
In the phase 3 J-FORCE study, Mr. Hashimoto and his colleagues evaluated olanzapine at 5 mg plus standard antiemetic therapy (APD) for the prevention of chemotherapy-induced nausea and vomiting.
The trial enrolled 710 patients, ages 22-75 years, who had malignant solid tumors and were receiving cisplatin-based chemotherapy for the first time. The patients were randomized to olanzapine plus APD or APD plus placebo.
There were 354 patients evaluable for efficacy in the olanzapine arm and 351 in the placebo arm. The primary endpoint was CR, which was defined as no vomiting and no rescue medications, in the delayed phase (24 hours to 120 hours).
The CR rate in the delayed phase was 79% in the olanzapine arm and 66% in the placebo arm (P less than .001). The CR rate in the acute phase (0 to 24 hours) was 95% and 89%, respectively (P equal to .002), and the overall CR rate was 78% and 64%, respectively (P less than .001).
The time to treatment failure was significantly longer in the olanzapine arm (P less than .001).
The rate of complete control in the overall period (0 to 120 hours) was 76% in the olanzapine arm and 61% in the placebo arm (P less than .001). Complete control was defined as no emesis, no rescue medication, and no nausea or low-grade nausea.
The rate of total control in the overall period was 59% in the olanzapine arm and 48% in the placebo arm (P = .005). Total control was defined as no emesis, no rescue medication, and no nausea.
Treatment-related adverse events (in the olanzapine and placebo arms, respectively) included constipation (15% and 11%), hiccups (10% and 6%), somnolence (43% and 33%), insomnia (5% and 7%), dizziness (8% and 3%), and dry mouth (21% and 9%).
Adverse events that occurred significantly more often with olanzapine were somnolence (P = .011), dizziness (P = .004), and dry mouth (P less than .001).
This study was sponsored by the Japan Agency for Medical Research and Development (AMED). Mr. Hashimoto said he had nothing to disclose. Other investigators involved in this study disclosed relationships with numerous pharmaceutical companies.
SOURCE: Hashimoto H et al. ASCO 2019. Abstract 11503.
CHICAGO – Olanzapine plus aprepitant, palonosetron, and dexamethasone (APD) can be considered a new standard antiemetic therapy for patients receiving cisplatin-based chemotherapy, according to a speaker at the annual meeting of the American Society for Clinical Oncology.
A 5 mg dose of olanzapine plus APD produced significantly higher complete response (CR) rates than APD plus placebo in a phase 3 trial, said Hironobu Hashimoto, BPharm, of the National Cancer Center Hospital in Tokyo.
In addition, olanzapine plus APD had a significantly longer time to treatment failure and produced higher rates of complete control and total control. However, rates of somnolence, dizziness, and dry mouth were significantly higher with olanzapine plus APD.
In the phase 3 J-FORCE study, Mr. Hashimoto and his colleagues evaluated olanzapine at 5 mg plus standard antiemetic therapy (APD) for the prevention of chemotherapy-induced nausea and vomiting.
The trial enrolled 710 patients, ages 22-75 years, who had malignant solid tumors and were receiving cisplatin-based chemotherapy for the first time. The patients were randomized to olanzapine plus APD or APD plus placebo.
There were 354 patients evaluable for efficacy in the olanzapine arm and 351 in the placebo arm. The primary endpoint was CR, which was defined as no vomiting and no rescue medications, in the delayed phase (24 hours to 120 hours).
The CR rate in the delayed phase was 79% in the olanzapine arm and 66% in the placebo arm (P less than .001). The CR rate in the acute phase (0 to 24 hours) was 95% and 89%, respectively (P equal to .002), and the overall CR rate was 78% and 64%, respectively (P less than .001).
The time to treatment failure was significantly longer in the olanzapine arm (P less than .001).
The rate of complete control in the overall period (0 to 120 hours) was 76% in the olanzapine arm and 61% in the placebo arm (P less than .001). Complete control was defined as no emesis, no rescue medication, and no nausea or low-grade nausea.
The rate of total control in the overall period was 59% in the olanzapine arm and 48% in the placebo arm (P = .005). Total control was defined as no emesis, no rescue medication, and no nausea.
Treatment-related adverse events (in the olanzapine and placebo arms, respectively) included constipation (15% and 11%), hiccups (10% and 6%), somnolence (43% and 33%), insomnia (5% and 7%), dizziness (8% and 3%), and dry mouth (21% and 9%).
Adverse events that occurred significantly more often with olanzapine were somnolence (P = .011), dizziness (P = .004), and dry mouth (P less than .001).
This study was sponsored by the Japan Agency for Medical Research and Development (AMED). Mr. Hashimoto said he had nothing to disclose. Other investigators involved in this study disclosed relationships with numerous pharmaceutical companies.
SOURCE: Hashimoto H et al. ASCO 2019. Abstract 11503.
CHICAGO – Olanzapine plus aprepitant, palonosetron, and dexamethasone (APD) can be considered a new standard antiemetic therapy for patients receiving cisplatin-based chemotherapy, according to a speaker at the annual meeting of the American Society for Clinical Oncology.
A 5 mg dose of olanzapine plus APD produced significantly higher complete response (CR) rates than APD plus placebo in a phase 3 trial, said Hironobu Hashimoto, BPharm, of the National Cancer Center Hospital in Tokyo.
In addition, olanzapine plus APD had a significantly longer time to treatment failure and produced higher rates of complete control and total control. However, rates of somnolence, dizziness, and dry mouth were significantly higher with olanzapine plus APD.
In the phase 3 J-FORCE study, Mr. Hashimoto and his colleagues evaluated olanzapine at 5 mg plus standard antiemetic therapy (APD) for the prevention of chemotherapy-induced nausea and vomiting.
The trial enrolled 710 patients, ages 22-75 years, who had malignant solid tumors and were receiving cisplatin-based chemotherapy for the first time. The patients were randomized to olanzapine plus APD or APD plus placebo.
There were 354 patients evaluable for efficacy in the olanzapine arm and 351 in the placebo arm. The primary endpoint was CR, which was defined as no vomiting and no rescue medications, in the delayed phase (24 hours to 120 hours).
The CR rate in the delayed phase was 79% in the olanzapine arm and 66% in the placebo arm (P less than .001). The CR rate in the acute phase (0 to 24 hours) was 95% and 89%, respectively (P equal to .002), and the overall CR rate was 78% and 64%, respectively (P less than .001).
The time to treatment failure was significantly longer in the olanzapine arm (P less than .001).
The rate of complete control in the overall period (0 to 120 hours) was 76% in the olanzapine arm and 61% in the placebo arm (P less than .001). Complete control was defined as no emesis, no rescue medication, and no nausea or low-grade nausea.
The rate of total control in the overall period was 59% in the olanzapine arm and 48% in the placebo arm (P = .005). Total control was defined as no emesis, no rescue medication, and no nausea.
Treatment-related adverse events (in the olanzapine and placebo arms, respectively) included constipation (15% and 11%), hiccups (10% and 6%), somnolence (43% and 33%), insomnia (5% and 7%), dizziness (8% and 3%), and dry mouth (21% and 9%).
Adverse events that occurred significantly more often with olanzapine were somnolence (P = .011), dizziness (P = .004), and dry mouth (P less than .001).
This study was sponsored by the Japan Agency for Medical Research and Development (AMED). Mr. Hashimoto said he had nothing to disclose. Other investigators involved in this study disclosed relationships with numerous pharmaceutical companies.
SOURCE: Hashimoto H et al. ASCO 2019. Abstract 11503.
REPORTING FROM ASCO 2019