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Apple cider vinegar soaks fall short in atopic dermatitis
, in a pilot split-arm study.
The aim of the study was to evaluate the effects of diluted apple cider vinegar application on transepidermal water loss (TEWL) and pH on skin affected by AD and on healthy skin, according to Lydia A. Luu of the department of dermatology at University of Virginia, Charlottesville, and colleagues. “Acetic acid, particularly apple cider vinegar, is prominent among emerging natural remedies used in AD. Therefore, determining the safety of this commonly used product is crucial,” they wrote in the study, published in Pediatric Dermatology.
In total, 11 patients with AD and 11 healthy controls were included; most of those with AD were considered mild (36.4%) or moderate (45.5%). Participants had not used systemic or topical antimicrobial treatments in the month preceding the study, and they were aged 12 years and older (mean ages were 20.6 years in the AD group and 28.8 years among controls). Those with AD had significantly elevated TEWL at baseline, compared with controls.
For 14 days, study participants soaked one forearm in dilute apple cider vinegar (0.5% acetic acid) and the other in tap water for 10 minutes daily. Changes in pH and TEWL before and after application were measured.
The researchers found that TEWL significantly increased immediately post treatment (at 0 and 15 minutes) in both groups, dropping to baseline at 30 minutes among those with AD and at 60 minutes among controls.
Skin pH was similar in both groups at baseline (4.86-4.88). After the cider vinegar soak, there was a transient reduction in skin pH among AD patients that lasted for 15 minutes among those with AD and 60 minutes in controls. This finding “suggests temporary acidification of the skin that has theoretical benefit of correcting disrupted skin pH in AD,” the authors wrote, noting that increased TEWL and alkaline skin pH is common among people with AD because of skin barrier dysfunction.
With respect to safety, 72.7% (16) of the participants experienced skin discomfort, mostly described as mild, limited to the vinegar-treated arm. After discontinuation, the majority of skin irritation resolved quickly, with no additional therapy.
The authors acknowledged two key limitations of the study were the homogeneous patient population and small sample size. “Although epidermal acidification would theoretically be beneficial in treating AD, our study shows that acidification by way of topical bathing in a 0.5% [apple cider vinegar] solution as performed in this study is not useful in AD treatment,” they wrote. “Further studies in a more diverse population will be necessary to fully characterize the risk/benefit profile of topical dilute apple cider vinegar treatments.”
The study was funded by the University of Virginia. The authors did not provide information on financial disclosures.
SOURCE: Luu LA et al. Pediatr Dermatol. 2019 Jul 22. doi: 10.1111/pde.13888.
, in a pilot split-arm study.
The aim of the study was to evaluate the effects of diluted apple cider vinegar application on transepidermal water loss (TEWL) and pH on skin affected by AD and on healthy skin, according to Lydia A. Luu of the department of dermatology at University of Virginia, Charlottesville, and colleagues. “Acetic acid, particularly apple cider vinegar, is prominent among emerging natural remedies used in AD. Therefore, determining the safety of this commonly used product is crucial,” they wrote in the study, published in Pediatric Dermatology.
In total, 11 patients with AD and 11 healthy controls were included; most of those with AD were considered mild (36.4%) or moderate (45.5%). Participants had not used systemic or topical antimicrobial treatments in the month preceding the study, and they were aged 12 years and older (mean ages were 20.6 years in the AD group and 28.8 years among controls). Those with AD had significantly elevated TEWL at baseline, compared with controls.
For 14 days, study participants soaked one forearm in dilute apple cider vinegar (0.5% acetic acid) and the other in tap water for 10 minutes daily. Changes in pH and TEWL before and after application were measured.
The researchers found that TEWL significantly increased immediately post treatment (at 0 and 15 minutes) in both groups, dropping to baseline at 30 minutes among those with AD and at 60 minutes among controls.
Skin pH was similar in both groups at baseline (4.86-4.88). After the cider vinegar soak, there was a transient reduction in skin pH among AD patients that lasted for 15 minutes among those with AD and 60 minutes in controls. This finding “suggests temporary acidification of the skin that has theoretical benefit of correcting disrupted skin pH in AD,” the authors wrote, noting that increased TEWL and alkaline skin pH is common among people with AD because of skin barrier dysfunction.
With respect to safety, 72.7% (16) of the participants experienced skin discomfort, mostly described as mild, limited to the vinegar-treated arm. After discontinuation, the majority of skin irritation resolved quickly, with no additional therapy.
The authors acknowledged two key limitations of the study were the homogeneous patient population and small sample size. “Although epidermal acidification would theoretically be beneficial in treating AD, our study shows that acidification by way of topical bathing in a 0.5% [apple cider vinegar] solution as performed in this study is not useful in AD treatment,” they wrote. “Further studies in a more diverse population will be necessary to fully characterize the risk/benefit profile of topical dilute apple cider vinegar treatments.”
The study was funded by the University of Virginia. The authors did not provide information on financial disclosures.
SOURCE: Luu LA et al. Pediatr Dermatol. 2019 Jul 22. doi: 10.1111/pde.13888.
, in a pilot split-arm study.
The aim of the study was to evaluate the effects of diluted apple cider vinegar application on transepidermal water loss (TEWL) and pH on skin affected by AD and on healthy skin, according to Lydia A. Luu of the department of dermatology at University of Virginia, Charlottesville, and colleagues. “Acetic acid, particularly apple cider vinegar, is prominent among emerging natural remedies used in AD. Therefore, determining the safety of this commonly used product is crucial,” they wrote in the study, published in Pediatric Dermatology.
In total, 11 patients with AD and 11 healthy controls were included; most of those with AD were considered mild (36.4%) or moderate (45.5%). Participants had not used systemic or topical antimicrobial treatments in the month preceding the study, and they were aged 12 years and older (mean ages were 20.6 years in the AD group and 28.8 years among controls). Those with AD had significantly elevated TEWL at baseline, compared with controls.
For 14 days, study participants soaked one forearm in dilute apple cider vinegar (0.5% acetic acid) and the other in tap water for 10 minutes daily. Changes in pH and TEWL before and after application were measured.
The researchers found that TEWL significantly increased immediately post treatment (at 0 and 15 minutes) in both groups, dropping to baseline at 30 minutes among those with AD and at 60 minutes among controls.
Skin pH was similar in both groups at baseline (4.86-4.88). After the cider vinegar soak, there was a transient reduction in skin pH among AD patients that lasted for 15 minutes among those with AD and 60 minutes in controls. This finding “suggests temporary acidification of the skin that has theoretical benefit of correcting disrupted skin pH in AD,” the authors wrote, noting that increased TEWL and alkaline skin pH is common among people with AD because of skin barrier dysfunction.
With respect to safety, 72.7% (16) of the participants experienced skin discomfort, mostly described as mild, limited to the vinegar-treated arm. After discontinuation, the majority of skin irritation resolved quickly, with no additional therapy.
The authors acknowledged two key limitations of the study were the homogeneous patient population and small sample size. “Although epidermal acidification would theoretically be beneficial in treating AD, our study shows that acidification by way of topical bathing in a 0.5% [apple cider vinegar] solution as performed in this study is not useful in AD treatment,” they wrote. “Further studies in a more diverse population will be necessary to fully characterize the risk/benefit profile of topical dilute apple cider vinegar treatments.”
The study was funded by the University of Virginia. The authors did not provide information on financial disclosures.
SOURCE: Luu LA et al. Pediatr Dermatol. 2019 Jul 22. doi: 10.1111/pde.13888.
FROM PEDIATRIC DERMATOLOGY
Four genetic variants link psychotic experiences to multiple mental disorders
Four genetic variations appear to link psychotic experiences with other psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders, a large genetic study has concluded.
, reported Sophie E. Legge, PhD, and colleagues. Their study was published in JAMA Psychiatry.
Although it is informative, the study is unlikely to expand the knowledge of schizophrenia-specific genetics.
“Consistent with other studies, the heritability estimate (1.71%) was low, and given that the variance explained in our polygenic risk analysis was also low, the finding suggests that understanding the genetics of psychotic experiences is unlikely to have an important effect on understanding the genetics of schizophrenia specifically,” wrote Dr. Legge, of the MRC Center for Neuropsychiatric Genetics and Genomics in the division of psychological medicine and clinical neurosciences at Cardiff (Wales) University, and colleagues.
The team conducted a genomewide association study (GWAS) using data from 127,966 individuals in the U.K. Biobank. Of these, 6,123 reported any psychotic experience, 2,143 reported distressing psychotic experiences, and 3,337 reported multiple experiences. The remainder served as controls. At the time of the biobank data collection, the subjects were a mean of 64 years of age; 56% were women.
First psychotic experience occurred at a mean of almost 32 years of age, but about a third reported that the first episode occurred before age 20, or that psychotic experiences had been happening ever since they could remember. Another third reported their first experience between ages 40 and 76 years.
The investigators conducted three GWAS studies: one for any psychotic experience, one for distressing experiences, and one for multiple experiences.
No significant genetic associations were found among those with multiple psychotic experiences, the authors said.
But they did find four variants significantly associated with the other experience categories.
Two variants were associated with any psychotic experience. Those with rs10994278, an intronic variant within Ankyrin-3 (ANK3), were 16% more likely to have a psychotic experience (odds ratio, 1.16). Those with intergenic variant rs549656827 were 39% less likely (OR, 0.61). “The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function,” the authors said. “ANK3 is one of strongest and most replicated genes for bipolar disorder, and variants within ANK3 have also been associated in the Psychiatric Genomics Consortium cross-disorder GWAS, and in a rare variant analysis of autism spectrum disorder.”
Two variants were linked to distressing psychotic experiences: rs75459873, intronic to cannabinoid receptor 2 (CNR2), decreased the risk by 34% (OR, 0.66). Intergenic variant rs3849810 increased the risk by 12% (OR, 1.12).
“CNR2 encodes for CB2, one of two well-characterized cannabinoid receptors. Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders, including schizophrenia and depression. The main psychoactive agent of cannabis, tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, while no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error.”
Also, significant genetic correlations were found between any psychotic experiences and major depressive disorder, autism spectrum disorder, ADHD, and schizophrenia. However, the polygenic risk scores for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and autism spectrum disorder, were low.
“We also considered individual psychotic symptoms and found that polygenic risk scores for schizophrenia, bipolar disorder, depression, and ADHD were more strongly associated with delusions of persecution than with the other psychotic symptoms.”
Those with distressing psychotic experiences tended to have more copy number variations (CNVs) associated with schizophrenia (OR, 2.04) and neurodevelopmental disorders (OR, 1.75). The team also found significant associations between distressing experiences and major depressive disorder, ADHD, autism spectrum disorder, and schizophrenia.
“We found particular enrichment of these [polygenic risk scores] in distressing psychotic experiences and for delusions of persecution,” they noted. “ ... All schizophrenia-associated [copy number variations] are also associated with neurodevelopmental disorders such as intellectual disability and autism.”
The study’s strengths include its large sample size. Among its limitations, the researchers said, are the study’s retrospective measurement of psychotic experiences based on self-report from a questionnaire that was online. Gathering the data in that way raised the likelihood of possible error, they said.
Dr. Legge reported having no disclosures.
SOURCE: Legge SE et al. JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2508.
The genetic links uncovered in this study offer an intriguing, but incomplete look at the risks of psychotic experiences and their complicated intertwinings with other mental disorders, wrote Albert R. Powers III, MD, PhD.
“Penetrance of the genes in question likely depends at least in part on environmental influences, some of which have been studied extensively,” he wrote. “Recently, some have proposed risk stratification by exposome – a composite score of relevant exposures that may increase risk for psychosis and is analogous to the polygenic risk score used [here].
“The combination of environmental and genetic composite scores may lead to improved insight into individualized pathways toward psychotic experiences, highlighting genetic vulnerabilities to specific stressors likely to lead to phenotypic expression. Ultimately, this will require a more sophisticated mapping between phenomenology and biology than currently exists.”
One approach would be to combine deep phenotyping and behavioral analyses in a framework that could link all relevant levels from symptoms to neurophysiology.
“One such framework is predictive processing theory, which is linked closely with the free energy principle and the Bayesian brain hypothesis and attempts to explain perceptual and cognitive phenomena as manifestations of a drive to maintain as accurate an internal model of one’s surroundings as possible by minimizing prediction errors. This relatively simple scheme makes specific – and, importantly, falsifiable – assessments of the mathematical signatures of neurotypical processes and the ways they might break down to produce specific psychiatric symptoms.”
Dr. Powers is an assistant professor at the department of psychiatry at Yale University, New Haven, Conn., and serves as medical director of the PRIME Psychosis Research Clinic at Yale. His comments came in an accompanying editorial (JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2391 ).
The genetic links uncovered in this study offer an intriguing, but incomplete look at the risks of psychotic experiences and their complicated intertwinings with other mental disorders, wrote Albert R. Powers III, MD, PhD.
“Penetrance of the genes in question likely depends at least in part on environmental influences, some of which have been studied extensively,” he wrote. “Recently, some have proposed risk stratification by exposome – a composite score of relevant exposures that may increase risk for psychosis and is analogous to the polygenic risk score used [here].
“The combination of environmental and genetic composite scores may lead to improved insight into individualized pathways toward psychotic experiences, highlighting genetic vulnerabilities to specific stressors likely to lead to phenotypic expression. Ultimately, this will require a more sophisticated mapping between phenomenology and biology than currently exists.”
One approach would be to combine deep phenotyping and behavioral analyses in a framework that could link all relevant levels from symptoms to neurophysiology.
“One such framework is predictive processing theory, which is linked closely with the free energy principle and the Bayesian brain hypothesis and attempts to explain perceptual and cognitive phenomena as manifestations of a drive to maintain as accurate an internal model of one’s surroundings as possible by minimizing prediction errors. This relatively simple scheme makes specific – and, importantly, falsifiable – assessments of the mathematical signatures of neurotypical processes and the ways they might break down to produce specific psychiatric symptoms.”
Dr. Powers is an assistant professor at the department of psychiatry at Yale University, New Haven, Conn., and serves as medical director of the PRIME Psychosis Research Clinic at Yale. His comments came in an accompanying editorial (JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2391 ).
The genetic links uncovered in this study offer an intriguing, but incomplete look at the risks of psychotic experiences and their complicated intertwinings with other mental disorders, wrote Albert R. Powers III, MD, PhD.
“Penetrance of the genes in question likely depends at least in part on environmental influences, some of which have been studied extensively,” he wrote. “Recently, some have proposed risk stratification by exposome – a composite score of relevant exposures that may increase risk for psychosis and is analogous to the polygenic risk score used [here].
“The combination of environmental and genetic composite scores may lead to improved insight into individualized pathways toward psychotic experiences, highlighting genetic vulnerabilities to specific stressors likely to lead to phenotypic expression. Ultimately, this will require a more sophisticated mapping between phenomenology and biology than currently exists.”
One approach would be to combine deep phenotyping and behavioral analyses in a framework that could link all relevant levels from symptoms to neurophysiology.
“One such framework is predictive processing theory, which is linked closely with the free energy principle and the Bayesian brain hypothesis and attempts to explain perceptual and cognitive phenomena as manifestations of a drive to maintain as accurate an internal model of one’s surroundings as possible by minimizing prediction errors. This relatively simple scheme makes specific – and, importantly, falsifiable – assessments of the mathematical signatures of neurotypical processes and the ways they might break down to produce specific psychiatric symptoms.”
Dr. Powers is an assistant professor at the department of psychiatry at Yale University, New Haven, Conn., and serves as medical director of the PRIME Psychosis Research Clinic at Yale. His comments came in an accompanying editorial (JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2391 ).
Four genetic variations appear to link psychotic experiences with other psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders, a large genetic study has concluded.
, reported Sophie E. Legge, PhD, and colleagues. Their study was published in JAMA Psychiatry.
Although it is informative, the study is unlikely to expand the knowledge of schizophrenia-specific genetics.
“Consistent with other studies, the heritability estimate (1.71%) was low, and given that the variance explained in our polygenic risk analysis was also low, the finding suggests that understanding the genetics of psychotic experiences is unlikely to have an important effect on understanding the genetics of schizophrenia specifically,” wrote Dr. Legge, of the MRC Center for Neuropsychiatric Genetics and Genomics in the division of psychological medicine and clinical neurosciences at Cardiff (Wales) University, and colleagues.
The team conducted a genomewide association study (GWAS) using data from 127,966 individuals in the U.K. Biobank. Of these, 6,123 reported any psychotic experience, 2,143 reported distressing psychotic experiences, and 3,337 reported multiple experiences. The remainder served as controls. At the time of the biobank data collection, the subjects were a mean of 64 years of age; 56% were women.
First psychotic experience occurred at a mean of almost 32 years of age, but about a third reported that the first episode occurred before age 20, or that psychotic experiences had been happening ever since they could remember. Another third reported their first experience between ages 40 and 76 years.
The investigators conducted three GWAS studies: one for any psychotic experience, one for distressing experiences, and one for multiple experiences.
No significant genetic associations were found among those with multiple psychotic experiences, the authors said.
But they did find four variants significantly associated with the other experience categories.
Two variants were associated with any psychotic experience. Those with rs10994278, an intronic variant within Ankyrin-3 (ANK3), were 16% more likely to have a psychotic experience (odds ratio, 1.16). Those with intergenic variant rs549656827 were 39% less likely (OR, 0.61). “The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function,” the authors said. “ANK3 is one of strongest and most replicated genes for bipolar disorder, and variants within ANK3 have also been associated in the Psychiatric Genomics Consortium cross-disorder GWAS, and in a rare variant analysis of autism spectrum disorder.”
Two variants were linked to distressing psychotic experiences: rs75459873, intronic to cannabinoid receptor 2 (CNR2), decreased the risk by 34% (OR, 0.66). Intergenic variant rs3849810 increased the risk by 12% (OR, 1.12).
“CNR2 encodes for CB2, one of two well-characterized cannabinoid receptors. Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders, including schizophrenia and depression. The main psychoactive agent of cannabis, tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, while no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error.”
Also, significant genetic correlations were found between any psychotic experiences and major depressive disorder, autism spectrum disorder, ADHD, and schizophrenia. However, the polygenic risk scores for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and autism spectrum disorder, were low.
“We also considered individual psychotic symptoms and found that polygenic risk scores for schizophrenia, bipolar disorder, depression, and ADHD were more strongly associated with delusions of persecution than with the other psychotic symptoms.”
Those with distressing psychotic experiences tended to have more copy number variations (CNVs) associated with schizophrenia (OR, 2.04) and neurodevelopmental disorders (OR, 1.75). The team also found significant associations between distressing experiences and major depressive disorder, ADHD, autism spectrum disorder, and schizophrenia.
“We found particular enrichment of these [polygenic risk scores] in distressing psychotic experiences and for delusions of persecution,” they noted. “ ... All schizophrenia-associated [copy number variations] are also associated with neurodevelopmental disorders such as intellectual disability and autism.”
The study’s strengths include its large sample size. Among its limitations, the researchers said, are the study’s retrospective measurement of psychotic experiences based on self-report from a questionnaire that was online. Gathering the data in that way raised the likelihood of possible error, they said.
Dr. Legge reported having no disclosures.
SOURCE: Legge SE et al. JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2508.
Four genetic variations appear to link psychotic experiences with other psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders, a large genetic study has concluded.
, reported Sophie E. Legge, PhD, and colleagues. Their study was published in JAMA Psychiatry.
Although it is informative, the study is unlikely to expand the knowledge of schizophrenia-specific genetics.
“Consistent with other studies, the heritability estimate (1.71%) was low, and given that the variance explained in our polygenic risk analysis was also low, the finding suggests that understanding the genetics of psychotic experiences is unlikely to have an important effect on understanding the genetics of schizophrenia specifically,” wrote Dr. Legge, of the MRC Center for Neuropsychiatric Genetics and Genomics in the division of psychological medicine and clinical neurosciences at Cardiff (Wales) University, and colleagues.
The team conducted a genomewide association study (GWAS) using data from 127,966 individuals in the U.K. Biobank. Of these, 6,123 reported any psychotic experience, 2,143 reported distressing psychotic experiences, and 3,337 reported multiple experiences. The remainder served as controls. At the time of the biobank data collection, the subjects were a mean of 64 years of age; 56% were women.
First psychotic experience occurred at a mean of almost 32 years of age, but about a third reported that the first episode occurred before age 20, or that psychotic experiences had been happening ever since they could remember. Another third reported their first experience between ages 40 and 76 years.
The investigators conducted three GWAS studies: one for any psychotic experience, one for distressing experiences, and one for multiple experiences.
No significant genetic associations were found among those with multiple psychotic experiences, the authors said.
But they did find four variants significantly associated with the other experience categories.
Two variants were associated with any psychotic experience. Those with rs10994278, an intronic variant within Ankyrin-3 (ANK3), were 16% more likely to have a psychotic experience (odds ratio, 1.16). Those with intergenic variant rs549656827 were 39% less likely (OR, 0.61). “The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function,” the authors said. “ANK3 is one of strongest and most replicated genes for bipolar disorder, and variants within ANK3 have also been associated in the Psychiatric Genomics Consortium cross-disorder GWAS, and in a rare variant analysis of autism spectrum disorder.”
Two variants were linked to distressing psychotic experiences: rs75459873, intronic to cannabinoid receptor 2 (CNR2), decreased the risk by 34% (OR, 0.66). Intergenic variant rs3849810 increased the risk by 12% (OR, 1.12).
“CNR2 encodes for CB2, one of two well-characterized cannabinoid receptors. Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders, including schizophrenia and depression. The main psychoactive agent of cannabis, tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, while no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error.”
Also, significant genetic correlations were found between any psychotic experiences and major depressive disorder, autism spectrum disorder, ADHD, and schizophrenia. However, the polygenic risk scores for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and autism spectrum disorder, were low.
“We also considered individual psychotic symptoms and found that polygenic risk scores for schizophrenia, bipolar disorder, depression, and ADHD were more strongly associated with delusions of persecution than with the other psychotic symptoms.”
Those with distressing psychotic experiences tended to have more copy number variations (CNVs) associated with schizophrenia (OR, 2.04) and neurodevelopmental disorders (OR, 1.75). The team also found significant associations between distressing experiences and major depressive disorder, ADHD, autism spectrum disorder, and schizophrenia.
“We found particular enrichment of these [polygenic risk scores] in distressing psychotic experiences and for delusions of persecution,” they noted. “ ... All schizophrenia-associated [copy number variations] are also associated with neurodevelopmental disorders such as intellectual disability and autism.”
The study’s strengths include its large sample size. Among its limitations, the researchers said, are the study’s retrospective measurement of psychotic experiences based on self-report from a questionnaire that was online. Gathering the data in that way raised the likelihood of possible error, they said.
Dr. Legge reported having no disclosures.
SOURCE: Legge SE et al. JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2508.
FROM JAMA PSYCHIATRY
NSCLC: Predicting benefit from immunotherapy plus chemo
In this edition of “How I will treat my next patient,” I highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.
TMB in nonsquamous NSCLC
Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.
Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.
In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.
Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.
Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.
How these results influence clinical practice
TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.
While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.
PD-L1 expression and overall survival
Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.
Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).
In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.
How these results influence clinical practice
As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.
To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.
TMB in nonsquamous NSCLC
Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.
Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.
In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.
Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.
Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.
How these results influence clinical practice
TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.
While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.
PD-L1 expression and overall survival
Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.
Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).
In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.
How these results influence clinical practice
As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.
To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.
TMB in nonsquamous NSCLC
Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.
Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.
In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.
Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.
Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.
How these results influence clinical practice
TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.
While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.
PD-L1 expression and overall survival
Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.
Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).
In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.
How these results influence clinical practice
As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.
To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
The Spillover Effect of EDs Closing
When an emergency department (ED) closes, neighboring hospitals—“bystander hospitals”—feel the effects, especially if they are already near or at full capacity: The health outcomes for their patients worsen, according to findings from a study funded by the National Heart, Lung, and Blood Institute (NHLBI).
The researchers examined outcomes for more than 1 million patients at nearly 4,000 hospitals in both urban and rural areas who had been affected by the closure or opening of an ED. The primary measures were 30-day, 90-day, and 1-year mortality rates, and 30-day readmission rates for heart attack. The researchers chose heart attacks because of the known benefits of timely treatment.
The researchers used changes in driving time between an ED and the next-closest one as a proxy for a closure or opening. If driving time increased, it meant a nearby ED had closed.
They found that when it took an additional 30 minutes or more to get to another hospital, the 1-year mortality rate in those receiving hospitals increased by 8% and the 30-day readmission rate by 6%. The likelihood of patients receiving an angioplasty or stent dropped by 4%.
However, the researchers also found that when an ED opened, the patients in the bystander hospitals benefited, experiencing a reduction in 1-year mortality by 5%. And the likelihood of their receiving percutaneous coronary intervention improved by 12%.
The study is believed to be the first to evaluate the impact of ED openings and closures on other hospitals. The lead author of the study, Renee Hsia, MD, said, “We now have evidence that hospital closures affect other hospitals, and they do so in different ways. Hospitals that are already crowded will likely be unable to maintain the same quality when a nearby emergency department closes.”
Limited resources at high-occupancy hospitals make them “sensitive to changes” in neighboring communities, the researchers say. “Hospital closures stress the health care infrastructure,” says Nicole Redmond, MD, PhD, MPH, a medical officer at NHLBI, “especially if the hospital is already caring for a socially and medically complex patient population and working at full capacity. As a result, such closures may inadvertently increase the health disparities that we are trying to mitigate.”
When an emergency department (ED) closes, neighboring hospitals—“bystander hospitals”—feel the effects, especially if they are already near or at full capacity: The health outcomes for their patients worsen, according to findings from a study funded by the National Heart, Lung, and Blood Institute (NHLBI).
The researchers examined outcomes for more than 1 million patients at nearly 4,000 hospitals in both urban and rural areas who had been affected by the closure or opening of an ED. The primary measures were 30-day, 90-day, and 1-year mortality rates, and 30-day readmission rates for heart attack. The researchers chose heart attacks because of the known benefits of timely treatment.
The researchers used changes in driving time between an ED and the next-closest one as a proxy for a closure or opening. If driving time increased, it meant a nearby ED had closed.
They found that when it took an additional 30 minutes or more to get to another hospital, the 1-year mortality rate in those receiving hospitals increased by 8% and the 30-day readmission rate by 6%. The likelihood of patients receiving an angioplasty or stent dropped by 4%.
However, the researchers also found that when an ED opened, the patients in the bystander hospitals benefited, experiencing a reduction in 1-year mortality by 5%. And the likelihood of their receiving percutaneous coronary intervention improved by 12%.
The study is believed to be the first to evaluate the impact of ED openings and closures on other hospitals. The lead author of the study, Renee Hsia, MD, said, “We now have evidence that hospital closures affect other hospitals, and they do so in different ways. Hospitals that are already crowded will likely be unable to maintain the same quality when a nearby emergency department closes.”
Limited resources at high-occupancy hospitals make them “sensitive to changes” in neighboring communities, the researchers say. “Hospital closures stress the health care infrastructure,” says Nicole Redmond, MD, PhD, MPH, a medical officer at NHLBI, “especially if the hospital is already caring for a socially and medically complex patient population and working at full capacity. As a result, such closures may inadvertently increase the health disparities that we are trying to mitigate.”
When an emergency department (ED) closes, neighboring hospitals—“bystander hospitals”—feel the effects, especially if they are already near or at full capacity: The health outcomes for their patients worsen, according to findings from a study funded by the National Heart, Lung, and Blood Institute (NHLBI).
The researchers examined outcomes for more than 1 million patients at nearly 4,000 hospitals in both urban and rural areas who had been affected by the closure or opening of an ED. The primary measures were 30-day, 90-day, and 1-year mortality rates, and 30-day readmission rates for heart attack. The researchers chose heart attacks because of the known benefits of timely treatment.
The researchers used changes in driving time between an ED and the next-closest one as a proxy for a closure or opening. If driving time increased, it meant a nearby ED had closed.
They found that when it took an additional 30 minutes or more to get to another hospital, the 1-year mortality rate in those receiving hospitals increased by 8% and the 30-day readmission rate by 6%. The likelihood of patients receiving an angioplasty or stent dropped by 4%.
However, the researchers also found that when an ED opened, the patients in the bystander hospitals benefited, experiencing a reduction in 1-year mortality by 5%. And the likelihood of their receiving percutaneous coronary intervention improved by 12%.
The study is believed to be the first to evaluate the impact of ED openings and closures on other hospitals. The lead author of the study, Renee Hsia, MD, said, “We now have evidence that hospital closures affect other hospitals, and they do so in different ways. Hospitals that are already crowded will likely be unable to maintain the same quality when a nearby emergency department closes.”
Limited resources at high-occupancy hospitals make them “sensitive to changes” in neighboring communities, the researchers say. “Hospital closures stress the health care infrastructure,” says Nicole Redmond, MD, PhD, MPH, a medical officer at NHLBI, “especially if the hospital is already caring for a socially and medically complex patient population and working at full capacity. As a result, such closures may inadvertently increase the health disparities that we are trying to mitigate.”
Gene recurrence score helps predict successful combination therapy for early breast cancer
alone in a study of 1,389 women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer.
“The 21-gene recurrence score (RS) assay provides prognostic information for distant recurrence in hormone-receptor–positive, ERBB2-negative early breast cancer that is independent of clinicopathologic features and is also predictive of chemotherapy benefit when the RS is high,” wrote Joseph A. Sparano, MD, of Montefiore Medical Center, New York, and his colleagues. However, little is known about how this risk score applies to women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer, they said.
In the study published in JAMA Oncology, they identified 1,389 women with a recurrence score of 26-100 (the definition of a high recurrence risk). The average age of the patients was 56 years, and 71% were postmenopausal.
In addition to receiving endocrine therapy, the women were randomized to no chemotherapy (89 patients) or one of several chemotherapy regimens including docetaxel/cyclophosphamide (589 patients), anthracycline without a taxane (334 patients), an anthracycline and taxane (244 patients), cyclophosphamide/methotrexate/5-fluorouracil (52 patients), and other regimens (81 patients). Among those treated with chemotherapy, overall survival (OS) at 5 years was 96% and estimated rates of freedom from recurrence of breast cancer at a distant site, and from a distant and/or local regional site, at 5 years were 93% and 91%, respectively. At 5 years, the estimated rate of invasive disease–free survival (IDFS) was 88%.
When broken down by chemotherapy regimen, 5-year rates of freedom from recurrence of breast cancer at a distant site ranged from 92.3% to 95.5%, except for 88.5% for the cyclophosphamide/methotrexate/5-fluorouracil (CMF) group; the rate was 92.6% for patients in the no-chemotherapy group.
The 5-year rates of IDFS ranged from 84% to 91.3% in the chemotherapy groups, compared with 79.7% in the no-chemotherapy group.
The expected rates of distant recurrence in the overall patient population if treated with endocrine therapy alone was 78.8% at 5 years and 65.4% at 9 years, the researchers said. Rates among the patients with an RS of 26-30 if treated with endocrine therapy alone were 89.6% at 5 years and 80.6% at 9 years; rates for those with an RS of 31-100 were 70.7% and 54% for 5 and 9 years, respectively.
The study findings were limited by several factors including a lack of randomization to endocrine therapy alone and the relatively short follow-up period, the researchers noted. However, strengths include the large sample size and high rate of compliance with chemotherapy.
The results support data from previous studies and “add to the evidence base supporting the use of the 21-gene RS assay to guide the use of adjuvant chemotherapy in patients with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer,” they concluded.
The study was supported in part by the National Cancer Institute, the Canadian Cancer Society Research Institute, the Breast Cancer Research Foundation, the Komen Foundation, and the Breast Cancer Research Stamp issued by the United States Postal Service. Dr. Sparano disclosed grants from the National Cancer Institute. Of the remaining authors, several disclosed receiving personal or speaker fees from the assay manufacturer, Genomic Health; one author received funding from the company during the study.
SOURCE: Sparano J et al. JAMA Oncol. 2019 Sep 30. doi: 10.1001/jamaoncol.2019.4794.
alone in a study of 1,389 women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer.
“The 21-gene recurrence score (RS) assay provides prognostic information for distant recurrence in hormone-receptor–positive, ERBB2-negative early breast cancer that is independent of clinicopathologic features and is also predictive of chemotherapy benefit when the RS is high,” wrote Joseph A. Sparano, MD, of Montefiore Medical Center, New York, and his colleagues. However, little is known about how this risk score applies to women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer, they said.
In the study published in JAMA Oncology, they identified 1,389 women with a recurrence score of 26-100 (the definition of a high recurrence risk). The average age of the patients was 56 years, and 71% were postmenopausal.
In addition to receiving endocrine therapy, the women were randomized to no chemotherapy (89 patients) or one of several chemotherapy regimens including docetaxel/cyclophosphamide (589 patients), anthracycline without a taxane (334 patients), an anthracycline and taxane (244 patients), cyclophosphamide/methotrexate/5-fluorouracil (52 patients), and other regimens (81 patients). Among those treated with chemotherapy, overall survival (OS) at 5 years was 96% and estimated rates of freedom from recurrence of breast cancer at a distant site, and from a distant and/or local regional site, at 5 years were 93% and 91%, respectively. At 5 years, the estimated rate of invasive disease–free survival (IDFS) was 88%.
When broken down by chemotherapy regimen, 5-year rates of freedom from recurrence of breast cancer at a distant site ranged from 92.3% to 95.5%, except for 88.5% for the cyclophosphamide/methotrexate/5-fluorouracil (CMF) group; the rate was 92.6% for patients in the no-chemotherapy group.
The 5-year rates of IDFS ranged from 84% to 91.3% in the chemotherapy groups, compared with 79.7% in the no-chemotherapy group.
The expected rates of distant recurrence in the overall patient population if treated with endocrine therapy alone was 78.8% at 5 years and 65.4% at 9 years, the researchers said. Rates among the patients with an RS of 26-30 if treated with endocrine therapy alone were 89.6% at 5 years and 80.6% at 9 years; rates for those with an RS of 31-100 were 70.7% and 54% for 5 and 9 years, respectively.
The study findings were limited by several factors including a lack of randomization to endocrine therapy alone and the relatively short follow-up period, the researchers noted. However, strengths include the large sample size and high rate of compliance with chemotherapy.
The results support data from previous studies and “add to the evidence base supporting the use of the 21-gene RS assay to guide the use of adjuvant chemotherapy in patients with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer,” they concluded.
The study was supported in part by the National Cancer Institute, the Canadian Cancer Society Research Institute, the Breast Cancer Research Foundation, the Komen Foundation, and the Breast Cancer Research Stamp issued by the United States Postal Service. Dr. Sparano disclosed grants from the National Cancer Institute. Of the remaining authors, several disclosed receiving personal or speaker fees from the assay manufacturer, Genomic Health; one author received funding from the company during the study.
SOURCE: Sparano J et al. JAMA Oncol. 2019 Sep 30. doi: 10.1001/jamaoncol.2019.4794.
alone in a study of 1,389 women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer.
“The 21-gene recurrence score (RS) assay provides prognostic information for distant recurrence in hormone-receptor–positive, ERBB2-negative early breast cancer that is independent of clinicopathologic features and is also predictive of chemotherapy benefit when the RS is high,” wrote Joseph A. Sparano, MD, of Montefiore Medical Center, New York, and his colleagues. However, little is known about how this risk score applies to women with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer, they said.
In the study published in JAMA Oncology, they identified 1,389 women with a recurrence score of 26-100 (the definition of a high recurrence risk). The average age of the patients was 56 years, and 71% were postmenopausal.
In addition to receiving endocrine therapy, the women were randomized to no chemotherapy (89 patients) or one of several chemotherapy regimens including docetaxel/cyclophosphamide (589 patients), anthracycline without a taxane (334 patients), an anthracycline and taxane (244 patients), cyclophosphamide/methotrexate/5-fluorouracil (52 patients), and other regimens (81 patients). Among those treated with chemotherapy, overall survival (OS) at 5 years was 96% and estimated rates of freedom from recurrence of breast cancer at a distant site, and from a distant and/or local regional site, at 5 years were 93% and 91%, respectively. At 5 years, the estimated rate of invasive disease–free survival (IDFS) was 88%.
When broken down by chemotherapy regimen, 5-year rates of freedom from recurrence of breast cancer at a distant site ranged from 92.3% to 95.5%, except for 88.5% for the cyclophosphamide/methotrexate/5-fluorouracil (CMF) group; the rate was 92.6% for patients in the no-chemotherapy group.
The 5-year rates of IDFS ranged from 84% to 91.3% in the chemotherapy groups, compared with 79.7% in the no-chemotherapy group.
The expected rates of distant recurrence in the overall patient population if treated with endocrine therapy alone was 78.8% at 5 years and 65.4% at 9 years, the researchers said. Rates among the patients with an RS of 26-30 if treated with endocrine therapy alone were 89.6% at 5 years and 80.6% at 9 years; rates for those with an RS of 31-100 were 70.7% and 54% for 5 and 9 years, respectively.
The study findings were limited by several factors including a lack of randomization to endocrine therapy alone and the relatively short follow-up period, the researchers noted. However, strengths include the large sample size and high rate of compliance with chemotherapy.
The results support data from previous studies and “add to the evidence base supporting the use of the 21-gene RS assay to guide the use of adjuvant chemotherapy in patients with hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer,” they concluded.
The study was supported in part by the National Cancer Institute, the Canadian Cancer Society Research Institute, the Breast Cancer Research Foundation, the Komen Foundation, and the Breast Cancer Research Stamp issued by the United States Postal Service. Dr. Sparano disclosed grants from the National Cancer Institute. Of the remaining authors, several disclosed receiving personal or speaker fees from the assay manufacturer, Genomic Health; one author received funding from the company during the study.
SOURCE: Sparano J et al. JAMA Oncol. 2019 Sep 30. doi: 10.1001/jamaoncol.2019.4794.
FROM JAMA ONCOLOGY
Heart disease raises risk of severe cutaneous adverse reactions to allopurinol
Researchers have found that patients with heart disease have an increased risk of hospitalization for severe cutaneous adverse reactions to allopurinol, with factors like chronic kidney disease and high initial dosage adding to that risk.
“Physicians who prescribe allopurinol should look for these risk factors so that they may consider initiating lower-dosage allopurinol and other precautions, which may prevent this rare but serious adverse reaction,” Chio Yokose, MD, of Massachusetts General Hospital in Boston and coauthors wrote in the Canadian Medical Association Journal.
To further investigate known associations between heart disease and severe cutaneous adverse reactions to allopurinol – including Stevens-Johnson syndrome and toxic epidermal necrolysis – the researchers used an administrative database known as Population Data BC to conduct a cohort study of allopurinol initiators in British Columbia between 1997 and 2015. Individuals with a history of severe cutaneous adverse reactions before starting allopurinol were excluded.
Of the 130,325 allopurinol users identified, 109 were hospitalized for allopurinol-associated severe cutaneous adverse reactions within 3 months of starting the drug. One in 655 allopurinol users with heart disease were admitted to the hospital for allopurinol-associated severe cutaneous adverse reaction (risk ratio = 1.53 per 1,000; 95% confidence interval, 1.10-2.06), compared with 1 in 1,548 allopurinol users without heart disease (risk ratio = 0.65 per 1,000; 95% CI, 0.50-0.82).
After multivariable analysis, other significant associations with hospital admission included chronic kidney disease (relative risk, 1.88; 95% CI, 1.17-3.02) and an initial allopurinol dosage greater than 100 mg/day (RR, 2.78; 95% CI, 1.75-4.43). In addition, patients with heart disease, chronic kidney disease, and an initial dosage greater than 100 mg/day had an 11-fold higher risk of hospital admission (RR, 11.13; 95% CI, 4.66-26.58).
The authors acknowledged their study’s limitations, including potential misclassification of reactions and comorbidities that can stem from a reliance on ICD codes. However, they also noted that “any misclassification is expected to be nondifferential” and bias results toward the null accordingly.
The study was funded by the Canadian Institutes of Health Research. One author reported receiving a grant from the National Institutes of Health and research support from AstraZeneca, along with consulting fees from Takeda, Selecta Biosciences, and Horizon. No other conflicts of interest were reported.
SOURCE: Yokose C et al. CMAJ. 2019 Sep 30. doi: 10.1503/cmaj.190339.
Researchers have found that patients with heart disease have an increased risk of hospitalization for severe cutaneous adverse reactions to allopurinol, with factors like chronic kidney disease and high initial dosage adding to that risk.
“Physicians who prescribe allopurinol should look for these risk factors so that they may consider initiating lower-dosage allopurinol and other precautions, which may prevent this rare but serious adverse reaction,” Chio Yokose, MD, of Massachusetts General Hospital in Boston and coauthors wrote in the Canadian Medical Association Journal.
To further investigate known associations between heart disease and severe cutaneous adverse reactions to allopurinol – including Stevens-Johnson syndrome and toxic epidermal necrolysis – the researchers used an administrative database known as Population Data BC to conduct a cohort study of allopurinol initiators in British Columbia between 1997 and 2015. Individuals with a history of severe cutaneous adverse reactions before starting allopurinol were excluded.
Of the 130,325 allopurinol users identified, 109 were hospitalized for allopurinol-associated severe cutaneous adverse reactions within 3 months of starting the drug. One in 655 allopurinol users with heart disease were admitted to the hospital for allopurinol-associated severe cutaneous adverse reaction (risk ratio = 1.53 per 1,000; 95% confidence interval, 1.10-2.06), compared with 1 in 1,548 allopurinol users without heart disease (risk ratio = 0.65 per 1,000; 95% CI, 0.50-0.82).
After multivariable analysis, other significant associations with hospital admission included chronic kidney disease (relative risk, 1.88; 95% CI, 1.17-3.02) and an initial allopurinol dosage greater than 100 mg/day (RR, 2.78; 95% CI, 1.75-4.43). In addition, patients with heart disease, chronic kidney disease, and an initial dosage greater than 100 mg/day had an 11-fold higher risk of hospital admission (RR, 11.13; 95% CI, 4.66-26.58).
The authors acknowledged their study’s limitations, including potential misclassification of reactions and comorbidities that can stem from a reliance on ICD codes. However, they also noted that “any misclassification is expected to be nondifferential” and bias results toward the null accordingly.
The study was funded by the Canadian Institutes of Health Research. One author reported receiving a grant from the National Institutes of Health and research support from AstraZeneca, along with consulting fees from Takeda, Selecta Biosciences, and Horizon. No other conflicts of interest were reported.
SOURCE: Yokose C et al. CMAJ. 2019 Sep 30. doi: 10.1503/cmaj.190339.
Researchers have found that patients with heart disease have an increased risk of hospitalization for severe cutaneous adverse reactions to allopurinol, with factors like chronic kidney disease and high initial dosage adding to that risk.
“Physicians who prescribe allopurinol should look for these risk factors so that they may consider initiating lower-dosage allopurinol and other precautions, which may prevent this rare but serious adverse reaction,” Chio Yokose, MD, of Massachusetts General Hospital in Boston and coauthors wrote in the Canadian Medical Association Journal.
To further investigate known associations between heart disease and severe cutaneous adverse reactions to allopurinol – including Stevens-Johnson syndrome and toxic epidermal necrolysis – the researchers used an administrative database known as Population Data BC to conduct a cohort study of allopurinol initiators in British Columbia between 1997 and 2015. Individuals with a history of severe cutaneous adverse reactions before starting allopurinol were excluded.
Of the 130,325 allopurinol users identified, 109 were hospitalized for allopurinol-associated severe cutaneous adverse reactions within 3 months of starting the drug. One in 655 allopurinol users with heart disease were admitted to the hospital for allopurinol-associated severe cutaneous adverse reaction (risk ratio = 1.53 per 1,000; 95% confidence interval, 1.10-2.06), compared with 1 in 1,548 allopurinol users without heart disease (risk ratio = 0.65 per 1,000; 95% CI, 0.50-0.82).
After multivariable analysis, other significant associations with hospital admission included chronic kidney disease (relative risk, 1.88; 95% CI, 1.17-3.02) and an initial allopurinol dosage greater than 100 mg/day (RR, 2.78; 95% CI, 1.75-4.43). In addition, patients with heart disease, chronic kidney disease, and an initial dosage greater than 100 mg/day had an 11-fold higher risk of hospital admission (RR, 11.13; 95% CI, 4.66-26.58).
The authors acknowledged their study’s limitations, including potential misclassification of reactions and comorbidities that can stem from a reliance on ICD codes. However, they also noted that “any misclassification is expected to be nondifferential” and bias results toward the null accordingly.
The study was funded by the Canadian Institutes of Health Research. One author reported receiving a grant from the National Institutes of Health and research support from AstraZeneca, along with consulting fees from Takeda, Selecta Biosciences, and Horizon. No other conflicts of interest were reported.
SOURCE: Yokose C et al. CMAJ. 2019 Sep 30. doi: 10.1503/cmaj.190339.
FROM THE CANADIAN MEDICAL ASSOCIATION JOURNAL
Immunotherapy duo extends survival in first line for advanced NSCLC
BARCELONA – Patients with than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.
Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.
The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.
Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.
CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.
The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.
Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).
In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.
The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.
Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.
Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.
Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.
“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.
“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.
He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).
Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.
“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.
“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.
The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.
SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.
BARCELONA – Patients with than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.
Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.
The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.
Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.
CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.
The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.
Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).
In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.
The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.
Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.
Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.
Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.
“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.
“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.
He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).
Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.
“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.
“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.
The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.
SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.
BARCELONA – Patients with than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.
Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.
The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.
Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.
CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.
The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.
Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).
In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.
The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.
Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.
Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.
Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.
“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.
“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.
He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).
Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.
“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.
“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.
The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.
SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.
REPORTING FROM ESMO 2019
PAOLA-1/ENGOT-ov25 trial: PARP inhibitor for maintenance improves PFS in advanced ovarian cancer
BARCELONA – Adding in the phase 3 PAOLA-1/ENGOT-ov25 trial.
The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.
Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.
The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.
In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.
“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”
The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.
“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.
Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.
Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.
The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.
Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.
The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.
During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.
“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.
Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.
“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”
In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”
Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”
In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”
As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.
The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.
SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
BARCELONA – Adding in the phase 3 PAOLA-1/ENGOT-ov25 trial.
The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.
Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.
The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.
In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.
“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”
The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.
“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.
Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.
Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.
The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.
Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.
The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.
During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.
“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.
Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.
“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”
In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”
Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”
In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”
As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.
The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.
SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
BARCELONA – Adding in the phase 3 PAOLA-1/ENGOT-ov25 trial.
The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.
Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.
The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.
In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.
“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”
The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.
“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.
Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.
Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.
The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.
Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.
The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.
During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.
“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.
Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.
“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”
In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”
Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”
In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”
As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.
The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.
SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
REPORTING FROM ESMO 2019
Cardiotoxicity after checkpoint inhibitor treatment seen early, linked to elevated biomarkers
PHILADELPHIA – , and occurred more frequently in patients with elevated biomarkers, in a retrospective cohort study reported at the annual scientific meeting of the Heart Failure Society of America.
The findings support monitoring of cardiac biomarkers in the initial phase of checkpoint inhibitor treatment to identify patient at high cardiac risk, according to Kalyan R. Chitturi, DO, a resident physician with the DeBakey Heart and Vascular Center, Houston Methodist Hospital, who presented the results.
“It’s the early period that warrants the closest monitoring, as within the first 30-40 days, there’s higher risk,” Dr. Chitturi said in an interview. “When there was a biomarker elevation, it markedly increased the risk of MACE, warranting a closer vigilance during that time period.”
The retrospective study conducted by Dr. Chitturi and colleagues included a total of 252 patients with lung cancer who had been treated at one of seven different sites in Houston Methodist Cancer Center between Aug. 1, 2015, and Aug. 1, 2018.
Immune checkpoint inhibitors did not significantly increase the risk of MACE, compared with other lung cancer therapies, with incidences of 13.3% and 10.3%, respectively (P = .632), the investigators found.
However, MACE did occur earlier in the checkpoint inhibitor group, at a median time to event of 40 days, compared with 118 days in the patients not treated with checkpoint inhibitors, they found.
Risk of MACE with checkpoint inhibitor treatment was increased in patients with elevated troponin (hazard ratio, 2.48; 95% confidence interval, 1.18-5.21; P = .017) or elevated brain natriuretic peptide (HR, 5.77; 95% CI, 2.70-12.35; P less than .001), according to multivariate logistic regression analysis results.
These results suggest biomarkers such as cardiac troponin and brain natriuretic peptide are warranted to monitor patients in the early phase of checkpoint inhibitor treatment, according to Dr. Chitturi. “In the cost-benefit ratio of often-lethal MACE, it’s well worth it to collect these,” he said in the interview.
The results corroborate findings from some other recent studies, he noted. These include a recent study that linked elevated serum troponin to myocarditis in patients treated with immune checkpoint inhibitors (J Am Coll Cardiol. 2018 Apr 24;71[16]:1755-64).
Dr. Chitturi and coauthors reported no disclosures related to their presentation at the HFSA meeting.
SOURCE: Chitturi KR et al. HFSA 2019, Abstract 127.
PHILADELPHIA – , and occurred more frequently in patients with elevated biomarkers, in a retrospective cohort study reported at the annual scientific meeting of the Heart Failure Society of America.
The findings support monitoring of cardiac biomarkers in the initial phase of checkpoint inhibitor treatment to identify patient at high cardiac risk, according to Kalyan R. Chitturi, DO, a resident physician with the DeBakey Heart and Vascular Center, Houston Methodist Hospital, who presented the results.
“It’s the early period that warrants the closest monitoring, as within the first 30-40 days, there’s higher risk,” Dr. Chitturi said in an interview. “When there was a biomarker elevation, it markedly increased the risk of MACE, warranting a closer vigilance during that time period.”
The retrospective study conducted by Dr. Chitturi and colleagues included a total of 252 patients with lung cancer who had been treated at one of seven different sites in Houston Methodist Cancer Center between Aug. 1, 2015, and Aug. 1, 2018.
Immune checkpoint inhibitors did not significantly increase the risk of MACE, compared with other lung cancer therapies, with incidences of 13.3% and 10.3%, respectively (P = .632), the investigators found.
However, MACE did occur earlier in the checkpoint inhibitor group, at a median time to event of 40 days, compared with 118 days in the patients not treated with checkpoint inhibitors, they found.
Risk of MACE with checkpoint inhibitor treatment was increased in patients with elevated troponin (hazard ratio, 2.48; 95% confidence interval, 1.18-5.21; P = .017) or elevated brain natriuretic peptide (HR, 5.77; 95% CI, 2.70-12.35; P less than .001), according to multivariate logistic regression analysis results.
These results suggest biomarkers such as cardiac troponin and brain natriuretic peptide are warranted to monitor patients in the early phase of checkpoint inhibitor treatment, according to Dr. Chitturi. “In the cost-benefit ratio of often-lethal MACE, it’s well worth it to collect these,” he said in the interview.
The results corroborate findings from some other recent studies, he noted. These include a recent study that linked elevated serum troponin to myocarditis in patients treated with immune checkpoint inhibitors (J Am Coll Cardiol. 2018 Apr 24;71[16]:1755-64).
Dr. Chitturi and coauthors reported no disclosures related to their presentation at the HFSA meeting.
SOURCE: Chitturi KR et al. HFSA 2019, Abstract 127.
PHILADELPHIA – , and occurred more frequently in patients with elevated biomarkers, in a retrospective cohort study reported at the annual scientific meeting of the Heart Failure Society of America.
The findings support monitoring of cardiac biomarkers in the initial phase of checkpoint inhibitor treatment to identify patient at high cardiac risk, according to Kalyan R. Chitturi, DO, a resident physician with the DeBakey Heart and Vascular Center, Houston Methodist Hospital, who presented the results.
“It’s the early period that warrants the closest monitoring, as within the first 30-40 days, there’s higher risk,” Dr. Chitturi said in an interview. “When there was a biomarker elevation, it markedly increased the risk of MACE, warranting a closer vigilance during that time period.”
The retrospective study conducted by Dr. Chitturi and colleagues included a total of 252 patients with lung cancer who had been treated at one of seven different sites in Houston Methodist Cancer Center between Aug. 1, 2015, and Aug. 1, 2018.
Immune checkpoint inhibitors did not significantly increase the risk of MACE, compared with other lung cancer therapies, with incidences of 13.3% and 10.3%, respectively (P = .632), the investigators found.
However, MACE did occur earlier in the checkpoint inhibitor group, at a median time to event of 40 days, compared with 118 days in the patients not treated with checkpoint inhibitors, they found.
Risk of MACE with checkpoint inhibitor treatment was increased in patients with elevated troponin (hazard ratio, 2.48; 95% confidence interval, 1.18-5.21; P = .017) or elevated brain natriuretic peptide (HR, 5.77; 95% CI, 2.70-12.35; P less than .001), according to multivariate logistic regression analysis results.
These results suggest biomarkers such as cardiac troponin and brain natriuretic peptide are warranted to monitor patients in the early phase of checkpoint inhibitor treatment, according to Dr. Chitturi. “In the cost-benefit ratio of often-lethal MACE, it’s well worth it to collect these,” he said in the interview.
The results corroborate findings from some other recent studies, he noted. These include a recent study that linked elevated serum troponin to myocarditis in patients treated with immune checkpoint inhibitors (J Am Coll Cardiol. 2018 Apr 24;71[16]:1755-64).
Dr. Chitturi and coauthors reported no disclosures related to their presentation at the HFSA meeting.
SOURCE: Chitturi KR et al. HFSA 2019, Abstract 127.
REPORTING FROM HFSA 2019
MitraClip learning curve may top 200 cases
SAN FRANCISCO – It took in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from November 2013 to March 2018.
“These findings demonstrate the key role of operator experience in optimizing outcomes” of transcatheter mitral valve repair (TMVr) with MitraClip (Abbott Structural), said investigators, led by Adnan Chhatriwalla, MD, an interventional cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.
“New operators may experience a ‘learning curve’ irrespective of the overall site experience or experience of other members of the Heart Team,” they wrote in the study (JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014).
“As TMVr becomes more prevalent in the U.S., it may be prudent for less experienced operators to be cognizant of where they sit on the ‘learning curve’ and to pay particular attention to case selection in their early experience, considering that more complex patients may be referred to more experienced centers for treatment when prudent,” they noted.
“The overall duration of the learning curve may exceed 200 cases,” Dr. Chhatriwalla said at the Transcatheter Cardiovascular Therapeutics annual meeting in a presentation that coincided with the study’s publication.
“This is a more complex procedure than [transcatheter aortic valve replacement], and the volume/outcome relationship is stronger. We are seeing issues that are related to early experience in low-volume programs. Public reporting so consumers can determine how many cases a center does is going to be critical,” said cardiothoracic surgeon Michael Mack, MD, director of the cardiovascular service line at a health system in Dallas, after the talk. He was one of the authors of the study.
The investigators compared outcomes among 549 operators who had done 1-25 MitraClip cases, 230 who had performed 26-50 cases, and 116 who had performed 50 or more.
Optimal procedural success – defined as less than or equal to 1+ residual mitral regurgitation (MR) without death or cardiac surgery – was 63.9%, 68.4%, and 75.1%, respectively, across the three groups (P less than .001). The “acceptable” procedural success rate – less than or equal to 2+ residual MR without death or cardiac surgery – was 91.4%, 92.4%, and 93.8% (P less than .001). No interaction was observed between the mechanism of mitral valve regurgitation and procedural outcomes.
Procedure time decreased as operators gained experience (145, 118, and 99 minutes), and atrial septal defect closure rates increased (0.9%, 1.4%, and 2.2%, respectively).
Composite complications rates also fell (9.7%, 8.1%, and 7.3%), driven mostly by less frequent cardiac perforation (1.0%, 1.1%, and 0.4%) and less frequent blood transfusion (9.6%, 8.6%, and 6.5%). The results were statistically significant.
“Adjusted learning curves for procedural success were visually evident after approximately 50 cases, and continued improvement in clinical outcomes was observed for the entire case sequence up to 200 cases,” the investigators wrote. The improvements could not be attributed to patient selection alone, they said.
More experienced operators were more likely to use more than one clip per case, and more frequently treated central and medial, as opposed to lateral, pathology. Operators with more than 50 cases were less likely to treat patients who had preexisting mitral stenosis or required home oxygen, and experienced operators were more likely to perform the procedure in unstable patients, when appropriate. The proportion of patients with functional MR – as opposed to degenerative disease – increased with increasing experience.
There were no statistically significant differences across the groups in stroke rates (P = .26), single-leaflet device attachments (P = .11), trans-septal complications (P = .25), urgent cardiac surgery (P = .42), or in-hospital mortality (P = .55).
Patients were a median of 81 years old, and most were white; 93% had 3+ or 4+ MR at baseline, and 86.3% had degenerative mitral disease. Two-thirds had atrial fibrillation/flutter.
The work was supported by the ACC/STS TVT Registry. Dr. Chhatriwalla is a proctor for Edwards Lifesciences and Medtronic, and is a speaker for Abbott, Edwards Lifesciences, and Medtronic. Dr. Mack has served as an investigator for Edwards Lifesciences and Abbott, and as a study chair for Medtronic. Other investigators reported similar industry disclosures.
The meeting is sponsored by the Cardiovascular Research Foundation.
SOURCE: Chhatriwalla A et. al. JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014.
SAN FRANCISCO – It took in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from November 2013 to March 2018.
“These findings demonstrate the key role of operator experience in optimizing outcomes” of transcatheter mitral valve repair (TMVr) with MitraClip (Abbott Structural), said investigators, led by Adnan Chhatriwalla, MD, an interventional cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.
“New operators may experience a ‘learning curve’ irrespective of the overall site experience or experience of other members of the Heart Team,” they wrote in the study (JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014).
“As TMVr becomes more prevalent in the U.S., it may be prudent for less experienced operators to be cognizant of where they sit on the ‘learning curve’ and to pay particular attention to case selection in their early experience, considering that more complex patients may be referred to more experienced centers for treatment when prudent,” they noted.
“The overall duration of the learning curve may exceed 200 cases,” Dr. Chhatriwalla said at the Transcatheter Cardiovascular Therapeutics annual meeting in a presentation that coincided with the study’s publication.
“This is a more complex procedure than [transcatheter aortic valve replacement], and the volume/outcome relationship is stronger. We are seeing issues that are related to early experience in low-volume programs. Public reporting so consumers can determine how many cases a center does is going to be critical,” said cardiothoracic surgeon Michael Mack, MD, director of the cardiovascular service line at a health system in Dallas, after the talk. He was one of the authors of the study.
The investigators compared outcomes among 549 operators who had done 1-25 MitraClip cases, 230 who had performed 26-50 cases, and 116 who had performed 50 or more.
Optimal procedural success – defined as less than or equal to 1+ residual mitral regurgitation (MR) without death or cardiac surgery – was 63.9%, 68.4%, and 75.1%, respectively, across the three groups (P less than .001). The “acceptable” procedural success rate – less than or equal to 2+ residual MR without death or cardiac surgery – was 91.4%, 92.4%, and 93.8% (P less than .001). No interaction was observed between the mechanism of mitral valve regurgitation and procedural outcomes.
Procedure time decreased as operators gained experience (145, 118, and 99 minutes), and atrial septal defect closure rates increased (0.9%, 1.4%, and 2.2%, respectively).
Composite complications rates also fell (9.7%, 8.1%, and 7.3%), driven mostly by less frequent cardiac perforation (1.0%, 1.1%, and 0.4%) and less frequent blood transfusion (9.6%, 8.6%, and 6.5%). The results were statistically significant.
“Adjusted learning curves for procedural success were visually evident after approximately 50 cases, and continued improvement in clinical outcomes was observed for the entire case sequence up to 200 cases,” the investigators wrote. The improvements could not be attributed to patient selection alone, they said.
More experienced operators were more likely to use more than one clip per case, and more frequently treated central and medial, as opposed to lateral, pathology. Operators with more than 50 cases were less likely to treat patients who had preexisting mitral stenosis or required home oxygen, and experienced operators were more likely to perform the procedure in unstable patients, when appropriate. The proportion of patients with functional MR – as opposed to degenerative disease – increased with increasing experience.
There were no statistically significant differences across the groups in stroke rates (P = .26), single-leaflet device attachments (P = .11), trans-septal complications (P = .25), urgent cardiac surgery (P = .42), or in-hospital mortality (P = .55).
Patients were a median of 81 years old, and most were white; 93% had 3+ or 4+ MR at baseline, and 86.3% had degenerative mitral disease. Two-thirds had atrial fibrillation/flutter.
The work was supported by the ACC/STS TVT Registry. Dr. Chhatriwalla is a proctor for Edwards Lifesciences and Medtronic, and is a speaker for Abbott, Edwards Lifesciences, and Medtronic. Dr. Mack has served as an investigator for Edwards Lifesciences and Abbott, and as a study chair for Medtronic. Other investigators reported similar industry disclosures.
The meeting is sponsored by the Cardiovascular Research Foundation.
SOURCE: Chhatriwalla A et. al. JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014.
SAN FRANCISCO – It took in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from November 2013 to March 2018.
“These findings demonstrate the key role of operator experience in optimizing outcomes” of transcatheter mitral valve repair (TMVr) with MitraClip (Abbott Structural), said investigators, led by Adnan Chhatriwalla, MD, an interventional cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.
“New operators may experience a ‘learning curve’ irrespective of the overall site experience or experience of other members of the Heart Team,” they wrote in the study (JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014).
“As TMVr becomes more prevalent in the U.S., it may be prudent for less experienced operators to be cognizant of where they sit on the ‘learning curve’ and to pay particular attention to case selection in their early experience, considering that more complex patients may be referred to more experienced centers for treatment when prudent,” they noted.
“The overall duration of the learning curve may exceed 200 cases,” Dr. Chhatriwalla said at the Transcatheter Cardiovascular Therapeutics annual meeting in a presentation that coincided with the study’s publication.
“This is a more complex procedure than [transcatheter aortic valve replacement], and the volume/outcome relationship is stronger. We are seeing issues that are related to early experience in low-volume programs. Public reporting so consumers can determine how many cases a center does is going to be critical,” said cardiothoracic surgeon Michael Mack, MD, director of the cardiovascular service line at a health system in Dallas, after the talk. He was one of the authors of the study.
The investigators compared outcomes among 549 operators who had done 1-25 MitraClip cases, 230 who had performed 26-50 cases, and 116 who had performed 50 or more.
Optimal procedural success – defined as less than or equal to 1+ residual mitral regurgitation (MR) without death or cardiac surgery – was 63.9%, 68.4%, and 75.1%, respectively, across the three groups (P less than .001). The “acceptable” procedural success rate – less than or equal to 2+ residual MR without death or cardiac surgery – was 91.4%, 92.4%, and 93.8% (P less than .001). No interaction was observed between the mechanism of mitral valve regurgitation and procedural outcomes.
Procedure time decreased as operators gained experience (145, 118, and 99 minutes), and atrial septal defect closure rates increased (0.9%, 1.4%, and 2.2%, respectively).
Composite complications rates also fell (9.7%, 8.1%, and 7.3%), driven mostly by less frequent cardiac perforation (1.0%, 1.1%, and 0.4%) and less frequent blood transfusion (9.6%, 8.6%, and 6.5%). The results were statistically significant.
“Adjusted learning curves for procedural success were visually evident after approximately 50 cases, and continued improvement in clinical outcomes was observed for the entire case sequence up to 200 cases,” the investigators wrote. The improvements could not be attributed to patient selection alone, they said.
More experienced operators were more likely to use more than one clip per case, and more frequently treated central and medial, as opposed to lateral, pathology. Operators with more than 50 cases were less likely to treat patients who had preexisting mitral stenosis or required home oxygen, and experienced operators were more likely to perform the procedure in unstable patients, when appropriate. The proportion of patients with functional MR – as opposed to degenerative disease – increased with increasing experience.
There were no statistically significant differences across the groups in stroke rates (P = .26), single-leaflet device attachments (P = .11), trans-septal complications (P = .25), urgent cardiac surgery (P = .42), or in-hospital mortality (P = .55).
Patients were a median of 81 years old, and most were white; 93% had 3+ or 4+ MR at baseline, and 86.3% had degenerative mitral disease. Two-thirds had atrial fibrillation/flutter.
The work was supported by the ACC/STS TVT Registry. Dr. Chhatriwalla is a proctor for Edwards Lifesciences and Medtronic, and is a speaker for Abbott, Edwards Lifesciences, and Medtronic. Dr. Mack has served as an investigator for Edwards Lifesciences and Abbott, and as a study chair for Medtronic. Other investigators reported similar industry disclosures.
The meeting is sponsored by the Cardiovascular Research Foundation.
SOURCE: Chhatriwalla A et. al. JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014.
REPORTING FROM TCT 2019