Susan London

Avacopan, an investigational oral inhibitor of complement activation, is efficacious and safe for treating antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, based on the results of the pivotal phase 3 ADVOCATE trial.

The trial results were reported in the opening plenary abstract session at the annual European Congress of Rheumatology, held online this year because of COVID-19.

“Standard of care for induction of remission includes high-dose glucocorticoids with either cyclophosphamide or rituximab. However, glucocorticoids are the major cause of treatment-related harm,” noted lead investigator Peter A. Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia.

The 331 patients in the trial had active ANCA-associated vasculitis (granulomatosis with polyangiitis or microscopic polyangiitis), either new onset or relapsed, with positivity for either proteinase 3 or myeloperoxidase antibodies and moderate to high disease activity.

They were randomized evenly to double-blind avacopan 30 mg or tapering prednisone from 60 mg/day to zero over 20 weeks, each combined either with rituximab (Rituxan) or with cyclophosphamide followed by azathioprine. Avacopan (formerly called CCX168) is a selective antagonist of the complement C5a receptor that has orphan-drug designation from the Food and Drug Administration for this disease.

Trial results showed that avacopan was noninferior to prednisone with respect to the week 26 rate of remission on the Birmingham Vasculitis Activity Score, with an estimate of common difference of 3.4%. And it was superior to prednisone with respect to the week 52 rate of sustained remission, which required remission from week 26 onward, with an estimate of common difference of 12.5%.

The avacopan group also had less glucocorticoid-related toxicity and, among patients with preexisting renal disease, greater improvement in renal function.

“This large, randomized trial met both of its primary endpoints. Important secondary endpoints were also achieved, with a very acceptable safety profile,” Dr. Merkel summarized.
 

Making sense of the results

The optimal duration of avacopan therapy is unclear, he noted. “We are still going to be learning how to use this drug, if it’s approved, in routine practice. But the data from the second 6 months – from week 26 to week 52 – implies that there is ongoing benefit to being on avacopan after remission is achieved.”

Avacopan worked similarly well regardless of disease status in ADVOCATE, according to Dr. Merkel. “We have not seen significant differences in efficacy of other drugs in our trials [by disease status], in the trials of ANCA-associated vasculitis. So I think we would treat moderate to serious disease similarly, whether it is new onset or recurrence, in terms of efficacy of the drug.”

“The topline phase 3 data from ADVOCATE sort of even exceeded my expectations in terms of the ability to show not just noninferiority, but superiority of avacopan at week 52 in maintaining sustained remission,” Lindsay S. Lally, MD, assistant professor of medicine at the Hospital for Special Surgery in New York, commented in an interview. “It’s spectacular to treat patients with this serious vasculitis without any steroids or with very minimal steroids, and see superiority at a year. That is really game changing.”

The ADVOCATE findings will likely pass muster with the FDA, according to Dr. Lally. “The bar that was set in terms of the coprimary endpoints was very stringent and in line with other registration trials, particularly the RAVE trial that led to the approval of rituximab,” she elaborated. “I don’t think there is any significant safety signal in the data related to avacopan.

“This study is going to move forward our ability to treat this disease effectively, as we have been able to do in some of our other vasculitis syndromes, by finding drugs that have significant steroid-sparing effects,” Dr. Lally predicted.
 

Study details

ADVOCATE results reported at the congress showed that the week 26 rate of disease remission was 72.3% with avacopan versus 70.1% with prednisone, with the difference falling within the 20% boundary for noninferiority (P < .0001) but missing the mark for superiority (P = .2387).

However, the week 52 rate of sustained disease remission was 65.7% versus 54.9%, respectively, yielding a difference in favor of avacopan that was statistically both noninferior (P < .0001) and superior (P = .0066).

At week 26, patients in the avacopan group had more favorable Glucocorticoid Toxicity Index scores for cumulative worsening (39.7 vs. 56.6; P = .0002) and for aggregate improvement (11.2 vs. 23.4; P = .008).

Among patients who had renal disease at baseline, those in the avacopan group had a greater increase in estimated glomerular filtration rate at week 52 (7.3 vs. 4.1 mL/min per 1.73 m²; P = .029).

“Particularly interesting is the fact that, even after week 26, when the patients were in remission, there was continued improvement in renal function,” Dr. Merkel noted.

Overall, avacopan had a good safety profile. “This was a sick population with many complications, but there were no important safety signals of the study medication,” he reported.

The avacopan and prednisone groups had a similar rate of severe adverse events (23.5% vs. 25.0%). But the former had lower rates of life-threatening adverse events (4.8% vs. 8.5%), adverse events potentially related to glucocorticoids (66.3% vs. 80.5%), deaths (1.2% vs. 2.4%), and deaths specifically caused by infection (0.6% vs. 1.2%).

The trial was sponsored by ChemoCentryx. Dr. Merkel disclosed receiving grant/research support from and consulting fees from ChemoCentryx, among other disclosures. Dr. Lally disclosed that she was an investigator in the trial.

SOURCE: Merkel PA et al. Ann Rheum Dis. 2020;79[suppl 1]:8, Abstract OP0011.

Avacopan, an investigational oral inhibitor of complement activation, is efficacious and safe for treating antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, based on the results of the pivotal phase 3 ADVOCATE trial.

The trial results were reported in the opening plenary abstract session at the annual European Congress of Rheumatology, held online this year because of COVID-19.

“Standard of care for induction of remission includes high-dose glucocorticoids with either cyclophosphamide or rituximab. However, glucocorticoids are the major cause of treatment-related harm,” noted lead investigator Peter A. Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia.

The 331 patients in the trial had active ANCA-associated vasculitis (granulomatosis with polyangiitis or microscopic polyangiitis), either new onset or relapsed, with positivity for either proteinase 3 or myeloperoxidase antibodies and moderate to high disease activity.

They were randomized evenly to double-blind avacopan 30 mg or tapering prednisone from 60 mg/day to zero over 20 weeks, each combined either with rituximab (Rituxan) or with cyclophosphamide followed by azathioprine. Avacopan (formerly called CCX168) is a selective antagonist of the complement C5a receptor that has orphan-drug designation from the Food and Drug Administration for this disease.

Trial results showed that avacopan was noninferior to prednisone with respect to the week 26 rate of remission on the Birmingham Vasculitis Activity Score, with an estimate of common difference of 3.4%. And it was superior to prednisone with respect to the week 52 rate of sustained remission, which required remission from week 26 onward, with an estimate of common difference of 12.5%.

The avacopan group also had less glucocorticoid-related toxicity and, among patients with preexisting renal disease, greater improvement in renal function.

“This large, randomized trial met both of its primary endpoints. Important secondary endpoints were also achieved, with a very acceptable safety profile,” Dr. Merkel summarized.
 

Making sense of the results

The optimal duration of avacopan therapy is unclear, he noted. “We are still going to be learning how to use this drug, if it’s approved, in routine practice. But the data from the second 6 months – from week 26 to week 52 – implies that there is ongoing benefit to being on avacopan after remission is achieved.”

Avacopan worked similarly well regardless of disease status in ADVOCATE, according to Dr. Merkel. “We have not seen significant differences in efficacy of other drugs in our trials [by disease status], in the trials of ANCA-associated vasculitis. So I think we would treat moderate to serious disease similarly, whether it is new onset or recurrence, in terms of efficacy of the drug.”

“The topline phase 3 data from ADVOCATE sort of even exceeded my expectations in terms of the ability to show not just noninferiority, but superiority of avacopan at week 52 in maintaining sustained remission,” Lindsay S. Lally, MD, assistant professor of medicine at the Hospital for Special Surgery in New York, commented in an interview. “It’s spectacular to treat patients with this serious vasculitis without any steroids or with very minimal steroids, and see superiority at a year. That is really game changing.”

The ADVOCATE findings will likely pass muster with the FDA, according to Dr. Lally. “The bar that was set in terms of the coprimary endpoints was very stringent and in line with other registration trials, particularly the RAVE trial that led to the approval of rituximab,” she elaborated. “I don’t think there is any significant safety signal in the data related to avacopan.

“This study is going to move forward our ability to treat this disease effectively, as we have been able to do in some of our other vasculitis syndromes, by finding drugs that have significant steroid-sparing effects,” Dr. Lally predicted.
 

Study details

ADVOCATE results reported at the congress showed that the week 26 rate of disease remission was 72.3% with avacopan versus 70.1% with prednisone, with the difference falling within the 20% boundary for noninferiority (P < .0001) but missing the mark for superiority (P = .2387).

However, the week 52 rate of sustained disease remission was 65.7% versus 54.9%, respectively, yielding a difference in favor of avacopan that was statistically both noninferior (P < .0001) and superior (P = .0066).

At week 26, patients in the avacopan group had more favorable Glucocorticoid Toxicity Index scores for cumulative worsening (39.7 vs. 56.6; P = .0002) and for aggregate improvement (11.2 vs. 23.4; P = .008).

Among patients who had renal disease at baseline, those in the avacopan group had a greater increase in estimated glomerular filtration rate at week 52 (7.3 vs. 4.1 mL/min per 1.73 m²; P = .029).

“Particularly interesting is the fact that, even after week 26, when the patients were in remission, there was continued improvement in renal function,” Dr. Merkel noted.

Overall, avacopan had a good safety profile. “This was a sick population with many complications, but there were no important safety signals of the study medication,” he reported.

The avacopan and prednisone groups had a similar rate of severe adverse events (23.5% vs. 25.0%). But the former had lower rates of life-threatening adverse events (4.8% vs. 8.5%), adverse events potentially related to glucocorticoids (66.3% vs. 80.5%), deaths (1.2% vs. 2.4%), and deaths specifically caused by infection (0.6% vs. 1.2%).

The trial was sponsored by ChemoCentryx. Dr. Merkel disclosed receiving grant/research support from and consulting fees from ChemoCentryx, among other disclosures. Dr. Lally disclosed that she was an investigator in the trial.

SOURCE: Merkel PA et al. Ann Rheum Dis. 2020;79[suppl 1]:8, Abstract OP0011.

Avacopan, an investigational oral inhibitor of complement activation, is efficacious and safe for treating antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, based on the results of the pivotal phase 3 ADVOCATE trial.

The trial results were reported in the opening plenary abstract session at the annual European Congress of Rheumatology, held online this year because of COVID-19.

“Standard of care for induction of remission includes high-dose glucocorticoids with either cyclophosphamide or rituximab. However, glucocorticoids are the major cause of treatment-related harm,” noted lead investigator Peter A. Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia.

The 331 patients in the trial had active ANCA-associated vasculitis (granulomatosis with polyangiitis or microscopic polyangiitis), either new onset or relapsed, with positivity for either proteinase 3 or myeloperoxidase antibodies and moderate to high disease activity.

They were randomized evenly to double-blind avacopan 30 mg or tapering prednisone from 60 mg/day to zero over 20 weeks, each combined either with rituximab (Rituxan) or with cyclophosphamide followed by azathioprine. Avacopan (formerly called CCX168) is a selective antagonist of the complement C5a receptor that has orphan-drug designation from the Food and Drug Administration for this disease.

Trial results showed that avacopan was noninferior to prednisone with respect to the week 26 rate of remission on the Birmingham Vasculitis Activity Score, with an estimate of common difference of 3.4%. And it was superior to prednisone with respect to the week 52 rate of sustained remission, which required remission from week 26 onward, with an estimate of common difference of 12.5%.

The avacopan group also had less glucocorticoid-related toxicity and, among patients with preexisting renal disease, greater improvement in renal function.

“This large, randomized trial met both of its primary endpoints. Important secondary endpoints were also achieved, with a very acceptable safety profile,” Dr. Merkel summarized.
 

Making sense of the results

The optimal duration of avacopan therapy is unclear, he noted. “We are still going to be learning how to use this drug, if it’s approved, in routine practice. But the data from the second 6 months – from week 26 to week 52 – implies that there is ongoing benefit to being on avacopan after remission is achieved.”

Avacopan worked similarly well regardless of disease status in ADVOCATE, according to Dr. Merkel. “We have not seen significant differences in efficacy of other drugs in our trials [by disease status], in the trials of ANCA-associated vasculitis. So I think we would treat moderate to serious disease similarly, whether it is new onset or recurrence, in terms of efficacy of the drug.”

“The topline phase 3 data from ADVOCATE sort of even exceeded my expectations in terms of the ability to show not just noninferiority, but superiority of avacopan at week 52 in maintaining sustained remission,” Lindsay S. Lally, MD, assistant professor of medicine at the Hospital for Special Surgery in New York, commented in an interview. “It’s spectacular to treat patients with this serious vasculitis without any steroids or with very minimal steroids, and see superiority at a year. That is really game changing.”

The ADVOCATE findings will likely pass muster with the FDA, according to Dr. Lally. “The bar that was set in terms of the coprimary endpoints was very stringent and in line with other registration trials, particularly the RAVE trial that led to the approval of rituximab,” she elaborated. “I don’t think there is any significant safety signal in the data related to avacopan.

“This study is going to move forward our ability to treat this disease effectively, as we have been able to do in some of our other vasculitis syndromes, by finding drugs that have significant steroid-sparing effects,” Dr. Lally predicted.
 

Study details

ADVOCATE results reported at the congress showed that the week 26 rate of disease remission was 72.3% with avacopan versus 70.1% with prednisone, with the difference falling within the 20% boundary for noninferiority (P < .0001) but missing the mark for superiority (P = .2387).

However, the week 52 rate of sustained disease remission was 65.7% versus 54.9%, respectively, yielding a difference in favor of avacopan that was statistically both noninferior (P < .0001) and superior (P = .0066).

At week 26, patients in the avacopan group had more favorable Glucocorticoid Toxicity Index scores for cumulative worsening (39.7 vs. 56.6; P = .0002) and for aggregate improvement (11.2 vs. 23.4; P = .008).

Among patients who had renal disease at baseline, those in the avacopan group had a greater increase in estimated glomerular filtration rate at week 52 (7.3 vs. 4.1 mL/min per 1.73 m²; P = .029).

“Particularly interesting is the fact that, even after week 26, when the patients were in remission, there was continued improvement in renal function,” Dr. Merkel noted.

Overall, avacopan had a good safety profile. “This was a sick population with many complications, but there were no important safety signals of the study medication,” he reported.

The avacopan and prednisone groups had a similar rate of severe adverse events (23.5% vs. 25.0%). But the former had lower rates of life-threatening adverse events (4.8% vs. 8.5%), adverse events potentially related to glucocorticoids (66.3% vs. 80.5%), deaths (1.2% vs. 2.4%), and deaths specifically caused by infection (0.6% vs. 1.2%).

The trial was sponsored by ChemoCentryx. Dr. Merkel disclosed receiving grant/research support from and consulting fees from ChemoCentryx, among other disclosures. Dr. Lally disclosed that she was an investigator in the trial.

SOURCE: Merkel PA et al. Ann Rheum Dis. 2020;79[suppl 1]:8, Abstract OP0011.

A new blood-based test performs well at detecting multiple types of cancers across stages and therefore has good potential for screening, according to a prospective case-control substudy.

Investigators led by Minetta C. Liu, MD, a medical oncologist with the Mayo Clinic, Rochester, Minn., studied 6,689 participants – 2,482 with cancers of more than 50 types and 4,207 without cancer – drawn from the Circulating Cell-free Genome Atlas Study and the STRIVE Study populations.

The investigators performed bisulfite sequencing that targeted informative methylation regions of plasma cell-free DNA (cfDNA), and developed and validated a molecular classifier using methylation patterns to detect cancer and determine its tissue of origin.

Test performance was assessed both for cancer overall and for a prespecified set of 12 cancers (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach) that account for about 63% of U.S. cancer deaths annually.

Results reported this week in the Annals of Oncology showed that the test had a specificity of 99.3% in the validation cohort, corresponding to a false-positive rate of just 0.7%.

Sensitivity for detecting stage I-III disease was 43.9% for cancer overall and 67.3% for the prespecified set of cancers accounting for the majority of U.S. cancer deaths.

Test sensitivity increased with stage both for cancer overall (18%, 43%, 81%, and 93% for stage I, II, III, and IV disease, respectively) and for the prespecified set of cancers (39%, 69%, 83%, and 92%, respectively).

The test was able to predict a tissue of origin in 96% of samples in which a cancerlike signal was detected, and in 93% of cases, that prediction was accurate.

Some of the patients who had cancer were symptomatic and therefore would not be considered a screening population, Dr. Liu and coinvestigators acknowledged. Also, the test’s potential for reducing mortality remains unknown, and 1-year follow-up to verify cancer-free status was not yet available for all of the individuals without cancer.

“Together, these data provide compelling evidence that targeted methylation analysis of cfDNA can detect and localize a broad range of nonmetastatic and metastatic cancer types including many common and deadly cancers that lack effective screening strategies,” they maintained. The test’s “specificity and sensitivity performance approach ... the goal for population-level screening.”

“Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies,” the investigators conclude. “Clinical validation in intended use populations is ongoing ... and a study has been initiated that is returning results to health care providers and patients ....”

Dr. Liu disclosed that the Mayo Clinic was compensated for her advisory board activities for GRAIL Inc. The study was supported by GRAIL, and by Princess Margaret Cancer Centre’s McCain Genitourinary BioBank in the department of surgical oncology.
 

SOURCE: Liu MC et al. Ann Oncol. 2020 Mar 31. doi: 10.1016/j.annonc.2020.02.011.

A new blood-based test performs well at detecting multiple types of cancers across stages and therefore has good potential for screening, according to a prospective case-control substudy.

Investigators led by Minetta C. Liu, MD, a medical oncologist with the Mayo Clinic, Rochester, Minn., studied 6,689 participants – 2,482 with cancers of more than 50 types and 4,207 without cancer – drawn from the Circulating Cell-free Genome Atlas Study and the STRIVE Study populations.

The investigators performed bisulfite sequencing that targeted informative methylation regions of plasma cell-free DNA (cfDNA), and developed and validated a molecular classifier using methylation patterns to detect cancer and determine its tissue of origin.

Test performance was assessed both for cancer overall and for a prespecified set of 12 cancers (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach) that account for about 63% of U.S. cancer deaths annually.

Results reported this week in the Annals of Oncology showed that the test had a specificity of 99.3% in the validation cohort, corresponding to a false-positive rate of just 0.7%.

Sensitivity for detecting stage I-III disease was 43.9% for cancer overall and 67.3% for the prespecified set of cancers accounting for the majority of U.S. cancer deaths.

Test sensitivity increased with stage both for cancer overall (18%, 43%, 81%, and 93% for stage I, II, III, and IV disease, respectively) and for the prespecified set of cancers (39%, 69%, 83%, and 92%, respectively).

The test was able to predict a tissue of origin in 96% of samples in which a cancerlike signal was detected, and in 93% of cases, that prediction was accurate.

Some of the patients who had cancer were symptomatic and therefore would not be considered a screening population, Dr. Liu and coinvestigators acknowledged. Also, the test’s potential for reducing mortality remains unknown, and 1-year follow-up to verify cancer-free status was not yet available for all of the individuals without cancer.

“Together, these data provide compelling evidence that targeted methylation analysis of cfDNA can detect and localize a broad range of nonmetastatic and metastatic cancer types including many common and deadly cancers that lack effective screening strategies,” they maintained. The test’s “specificity and sensitivity performance approach ... the goal for population-level screening.”

“Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies,” the investigators conclude. “Clinical validation in intended use populations is ongoing ... and a study has been initiated that is returning results to health care providers and patients ....”

Dr. Liu disclosed that the Mayo Clinic was compensated for her advisory board activities for GRAIL Inc. The study was supported by GRAIL, and by Princess Margaret Cancer Centre’s McCain Genitourinary BioBank in the department of surgical oncology.
 

SOURCE: Liu MC et al. Ann Oncol. 2020 Mar 31. doi: 10.1016/j.annonc.2020.02.011.

A new blood-based test performs well at detecting multiple types of cancers across stages and therefore has good potential for screening, according to a prospective case-control substudy.

Investigators led by Minetta C. Liu, MD, a medical oncologist with the Mayo Clinic, Rochester, Minn., studied 6,689 participants – 2,482 with cancers of more than 50 types and 4,207 without cancer – drawn from the Circulating Cell-free Genome Atlas Study and the STRIVE Study populations.

The investigators performed bisulfite sequencing that targeted informative methylation regions of plasma cell-free DNA (cfDNA), and developed and validated a molecular classifier using methylation patterns to detect cancer and determine its tissue of origin.

Test performance was assessed both for cancer overall and for a prespecified set of 12 cancers (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach) that account for about 63% of U.S. cancer deaths annually.

Results reported this week in the Annals of Oncology showed that the test had a specificity of 99.3% in the validation cohort, corresponding to a false-positive rate of just 0.7%.

Sensitivity for detecting stage I-III disease was 43.9% for cancer overall and 67.3% for the prespecified set of cancers accounting for the majority of U.S. cancer deaths.

Test sensitivity increased with stage both for cancer overall (18%, 43%, 81%, and 93% for stage I, II, III, and IV disease, respectively) and for the prespecified set of cancers (39%, 69%, 83%, and 92%, respectively).

The test was able to predict a tissue of origin in 96% of samples in which a cancerlike signal was detected, and in 93% of cases, that prediction was accurate.

Some of the patients who had cancer were symptomatic and therefore would not be considered a screening population, Dr. Liu and coinvestigators acknowledged. Also, the test’s potential for reducing mortality remains unknown, and 1-year follow-up to verify cancer-free status was not yet available for all of the individuals without cancer.

“Together, these data provide compelling evidence that targeted methylation analysis of cfDNA can detect and localize a broad range of nonmetastatic and metastatic cancer types including many common and deadly cancers that lack effective screening strategies,” they maintained. The test’s “specificity and sensitivity performance approach ... the goal for population-level screening.”

“Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies,” the investigators conclude. “Clinical validation in intended use populations is ongoing ... and a study has been initiated that is returning results to health care providers and patients ....”

Dr. Liu disclosed that the Mayo Clinic was compensated for her advisory board activities for GRAIL Inc. The study was supported by GRAIL, and by Princess Margaret Cancer Centre’s McCain Genitourinary BioBank in the department of surgical oncology.
 

SOURCE: Liu MC et al. Ann Oncol. 2020 Mar 31. doi: 10.1016/j.annonc.2020.02.011.

Older adults exposed to air pollution long term – even at fairly low levels – have an increased risk of dementia, and cardiovascular disease (CVD) appears to both modify and mediate this association, according to the results of the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) study.

Virtually all of the association between air pollution and dementia seemed to occur through the presence or the development of cardiovascular disease, which suggests a need to optimize treatment of concurrent cardiovascular disease and risk-factor control in older adults at higher risk for dementia and living in polluted urban areas, said lead author Giulia Grande, MD, a researcher at the Aging Research Center, Karolinska Institutet and Stockholm University, in Solna, Sweden.

In the longitudinal, population-based cohort study, investigators studied 2,927 randomly selected residents in a district of Stockholm who were aged 60 years or older (mean, 74.1 years), lived at home or in institutions, and were free of dementia at baseline (March 2001 through August 2004).

The investigators assessed the participants’ exposure to two major air pollutants – particulate matter ≤2.5 mcm and nitrogen oxide – yearly starting in 1990, from outdoor levels at their residential addresses. Both pollutants are generated by road traffic, among other sources.

Results reported in JAMA Neurology showed that, with a mean follow-up of 6.01 years, 12.4% of the older adults received a dementia diagnosis.

Dementia risk increased with the level of air pollutants at their residential address in the past, with strongest associations seen for exposure in the preceding 5 years: The hazard ratio (HR) for dementia was 1.54 for an interquartile range difference of 0.88 mcg/m³ in particulate matter ≤2.5 mcm and 1.14 for an interquartile range difference of 8.35 mcg/m³ in nitrogen oxide during that time period.

Of note, the study cohort lived in an area having “comparatively good ambient air quality” in which restrictions on air pollution have increased in recent decades, Dr. Grande and coinvestigators noted. “Interestingly, the higher limit reported herein is not only below the current European limit for fine particulate matter but also below the US standard. In other words, we were able to establish harmful effects at levels below current standards,” they wrote.

In analyses of effect modification, the elevation of risk related to particulate matter ≤2.5 mcm exposure and nitrogen oxide exposure was significantly greater among older adults who had heart failure (HRs, 1.93 and 1.43, respectively). Risk was marginally greater among those with ischemic heart disease (HRs, 1.67 and 1.36, respectively).

Analyses of potential mediators showed that preceding stroke accounted for the largest share of all dementia cases related to particulate matter ≤2.5 mcm exposure, at 49.4%.

The stronger association for exposure in the past 5 years is noteworthy for the big picture, they added. “From a policy point of view, this result is encouraging because it might imply that reducing air pollutant levels today could yield better outcomes already in the shorter term, reinforcing the need for appropriately set air quality standards,” they said.

Dr. Grande disclosed no relevant conflicts of interest. The study was funded by the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K); the Swedish Ministry of Health and Social Affairs; the participating County Councils and Municipalities; the Swedish Research Council; funding for doctoral education from the Karolinska Institutet; and the Swedish Research Council for Health, Working Life and Welfare.

SOURCE: Grande G et al. JAMA Neurol. 2020. doi:10.1001/jamaneurol.2019.4914.
 

Older adults exposed to air pollution long term – even at fairly low levels – have an increased risk of dementia, and cardiovascular disease (CVD) appears to both modify and mediate this association, according to the results of the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) study.

Virtually all of the association between air pollution and dementia seemed to occur through the presence or the development of cardiovascular disease, which suggests a need to optimize treatment of concurrent cardiovascular disease and risk-factor control in older adults at higher risk for dementia and living in polluted urban areas, said lead author Giulia Grande, MD, a researcher at the Aging Research Center, Karolinska Institutet and Stockholm University, in Solna, Sweden.

In the longitudinal, population-based cohort study, investigators studied 2,927 randomly selected residents in a district of Stockholm who were aged 60 years or older (mean, 74.1 years), lived at home or in institutions, and were free of dementia at baseline (March 2001 through August 2004).

The investigators assessed the participants’ exposure to two major air pollutants – particulate matter ≤2.5 mcm and nitrogen oxide – yearly starting in 1990, from outdoor levels at their residential addresses. Both pollutants are generated by road traffic, among other sources.

Results reported in JAMA Neurology showed that, with a mean follow-up of 6.01 years, 12.4% of the older adults received a dementia diagnosis.

Dementia risk increased with the level of air pollutants at their residential address in the past, with strongest associations seen for exposure in the preceding 5 years: The hazard ratio (HR) for dementia was 1.54 for an interquartile range difference of 0.88 mcg/m³ in particulate matter ≤2.5 mcm and 1.14 for an interquartile range difference of 8.35 mcg/m³ in nitrogen oxide during that time period.

Of note, the study cohort lived in an area having “comparatively good ambient air quality” in which restrictions on air pollution have increased in recent decades, Dr. Grande and coinvestigators noted. “Interestingly, the higher limit reported herein is not only below the current European limit for fine particulate matter but also below the US standard. In other words, we were able to establish harmful effects at levels below current standards,” they wrote.

In analyses of effect modification, the elevation of risk related to particulate matter ≤2.5 mcm exposure and nitrogen oxide exposure was significantly greater among older adults who had heart failure (HRs, 1.93 and 1.43, respectively). Risk was marginally greater among those with ischemic heart disease (HRs, 1.67 and 1.36, respectively).

Analyses of potential mediators showed that preceding stroke accounted for the largest share of all dementia cases related to particulate matter ≤2.5 mcm exposure, at 49.4%.

The stronger association for exposure in the past 5 years is noteworthy for the big picture, they added. “From a policy point of view, this result is encouraging because it might imply that reducing air pollutant levels today could yield better outcomes already in the shorter term, reinforcing the need for appropriately set air quality standards,” they said.

Dr. Grande disclosed no relevant conflicts of interest. The study was funded by the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K); the Swedish Ministry of Health and Social Affairs; the participating County Councils and Municipalities; the Swedish Research Council; funding for doctoral education from the Karolinska Institutet; and the Swedish Research Council for Health, Working Life and Welfare.

SOURCE: Grande G et al. JAMA Neurol. 2020. doi:10.1001/jamaneurol.2019.4914.
 

Older adults exposed to air pollution long term – even at fairly low levels – have an increased risk of dementia, and cardiovascular disease (CVD) appears to both modify and mediate this association, according to the results of the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) study.

Virtually all of the association between air pollution and dementia seemed to occur through the presence or the development of cardiovascular disease, which suggests a need to optimize treatment of concurrent cardiovascular disease and risk-factor control in older adults at higher risk for dementia and living in polluted urban areas, said lead author Giulia Grande, MD, a researcher at the Aging Research Center, Karolinska Institutet and Stockholm University, in Solna, Sweden.

In the longitudinal, population-based cohort study, investigators studied 2,927 randomly selected residents in a district of Stockholm who were aged 60 years or older (mean, 74.1 years), lived at home or in institutions, and were free of dementia at baseline (March 2001 through August 2004).

The investigators assessed the participants’ exposure to two major air pollutants – particulate matter ≤2.5 mcm and nitrogen oxide – yearly starting in 1990, from outdoor levels at their residential addresses. Both pollutants are generated by road traffic, among other sources.

Results reported in JAMA Neurology showed that, with a mean follow-up of 6.01 years, 12.4% of the older adults received a dementia diagnosis.

Dementia risk increased with the level of air pollutants at their residential address in the past, with strongest associations seen for exposure in the preceding 5 years: The hazard ratio (HR) for dementia was 1.54 for an interquartile range difference of 0.88 mcg/m³ in particulate matter ≤2.5 mcm and 1.14 for an interquartile range difference of 8.35 mcg/m³ in nitrogen oxide during that time period.

Of note, the study cohort lived in an area having “comparatively good ambient air quality” in which restrictions on air pollution have increased in recent decades, Dr. Grande and coinvestigators noted. “Interestingly, the higher limit reported herein is not only below the current European limit for fine particulate matter but also below the US standard. In other words, we were able to establish harmful effects at levels below current standards,” they wrote.

In analyses of effect modification, the elevation of risk related to particulate matter ≤2.5 mcm exposure and nitrogen oxide exposure was significantly greater among older adults who had heart failure (HRs, 1.93 and 1.43, respectively). Risk was marginally greater among those with ischemic heart disease (HRs, 1.67 and 1.36, respectively).

Analyses of potential mediators showed that preceding stroke accounted for the largest share of all dementia cases related to particulate matter ≤2.5 mcm exposure, at 49.4%.

The stronger association for exposure in the past 5 years is noteworthy for the big picture, they added. “From a policy point of view, this result is encouraging because it might imply that reducing air pollutant levels today could yield better outcomes already in the shorter term, reinforcing the need for appropriately set air quality standards,” they said.

Dr. Grande disclosed no relevant conflicts of interest. The study was funded by the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K); the Swedish Ministry of Health and Social Affairs; the participating County Councils and Municipalities; the Swedish Research Council; funding for doctoral education from the Karolinska Institutet; and the Swedish Research Council for Health, Working Life and Welfare.

SOURCE: Grande G et al. JAMA Neurol. 2020. doi:10.1001/jamaneurol.2019.4914.
 

Pertuzumab has a durable benefit in patients with metastatic HER2-positive breast cancer when added to trastuzumab and docetaxel as first-line therapy, with nearly 40% of patients achieving long-term survival, the CLEOPATRA end-of-study analysis shows.

The regimen, combining dual HER2 targeting with chemotherapy, became standard of care in this population as a result of its good efficacy and safety relative to placebo, first established in the phase 3, randomized trial 8 years ago (N Engl J Med. 2012;366:109-19).

Trial updates since then, most recently at a median follow-up of 50 months (N Engl J Med. 2015;372:724-34), have shown clear progression-free and overall survival benefits, with acceptable cardiac and other toxicity.

Investigators led by Sandra M. Swain, MD, of Georgetown University, Washington, performed a final analysis of data from the 808 patients in CLEOPATRA, now at a median follow-up of 99.9 months.

Results reported in The Lancet Oncology showed that, compared with placebo, pertuzumab prolonged investigator-assessed progression-free survival by 6.3 months (the same as that seen in the previous update) and prolonged overall survival by 16.3 months (up from 15.7 months in the previous update).

At 8 years, 37% of patients in the pertuzumab group were still alive, and 16% were still alive without progression.

“The combination of pertuzumab, trastuzumab, and docetaxel remains the standard of care for the first-line treatment of HER2-positive metastatic breast cancer, owing to its overall survival benefits and maintained long-term overall and cardiac safety,” Dr. Swain and coinvestigators concluded. “Prospective identification of patients who will be long-term responders to treatment is an area for future research.”

In an accompanying comment, Matteo Lambertini, MD, PhD, of IRCCS Ospedale Policlinico San Martino in Genova, Italy, and Ines Vaz-Luis, MD, of Institut Gustave Roussy in Villejuif, France, contended that these results, “which are also observed in real-world datasets, challenge the concept of HER2-positive metastatic breast cancer being an incurable disease and open the path to several interconnected clinical and research questions.”

Those questions include the optimal duration of anti-HER2 maintenance therapy in patients without disease progression, best strategies for combining this systemic therapy with local treatment to further improve survival, and new markers to better identify patients likely to be long-term responders, who might benefit from a curative approach, the authors elaborated. They noted that more than half of CLEOPATRA patients had de novo stage IV disease.

“The performance of the current standard pertuzumab-based first-line treatment in patients previously exposed to adjuvant or neoadjuvant anti-HER2 therapy remains to be clarified,” the authors wrote. “Results from several ongoing prospective cohort studies investigating real-world patterns of care and outcomes of patients with HER2-positive metastatic breast cancer will help to clarify this important issue and optimize treatment sequencing.”
 

Study details

The end-of-study analysis showed that median progression-free survival was 18.7 months with pertuzumab and 12.4 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.59-0.81). The 8-year landmark progression-free survival rate was 16% with the former and 10% with the latter.

The median overall survival was 57.1 months with pertuzumab and 40.8 months with placebo (HR, 0.69; 95% CI, 0.58-0.82). The 8-year landmark overall survival rate was 37% with the former and 23% with the latter.

A comparison of patients who did and did not achieve long-term response showed that, in both treatment groups, the former more often had tumors that were 3+ positive by HER2 immunohistochemistry and PIK3CA wild-type tumors. The leading grade 3 or 4 adverse event was neutropenia, seen in 49% of patients in the pertuzumab group and 46% of those in the placebo group. The rate of treatment-related death was 1% and 2%, respectively.

Since the last update, only two additional serious adverse events were reported: one case of heart failure and one case of symptomatic left ventricular systolic dysfunction in patients given pertuzumab.

The CLEOPATRA trial was funded by F. Hoffmann-La Roche and Genentech. Dr. Swain and coauthors disclosed relationships with these and other companies. Dr. Lambertini disclosed relationships with Roche, Theramex, and Takeda. Dr. Vaz-Luis disclosed relationships with AstraZeneca, Kephren, and Novartis.

SOURCE: Swain SM et al. Lancet Oncol. 2020 Mar 12. doi: 10.1016/S1470-2045(19)30863-0; Lambertini M et al. Lancet Oncol. 2020 Mar 12. doi: 10.1016/S1470-2045(20)30058-9.

Pertuzumab has a durable benefit in patients with metastatic HER2-positive breast cancer when added to trastuzumab and docetaxel as first-line therapy, with nearly 40% of patients achieving long-term survival, the CLEOPATRA end-of-study analysis shows.

The regimen, combining dual HER2 targeting with chemotherapy, became standard of care in this population as a result of its good efficacy and safety relative to placebo, first established in the phase 3, randomized trial 8 years ago (N Engl J Med. 2012;366:109-19).

Trial updates since then, most recently at a median follow-up of 50 months (N Engl J Med. 2015;372:724-34), have shown clear progression-free and overall survival benefits, with acceptable cardiac and other toxicity.

Investigators led by Sandra M. Swain, MD, of Georgetown University, Washington, performed a final analysis of data from the 808 patients in CLEOPATRA, now at a median follow-up of 99.9 months.

Results reported in The Lancet Oncology showed that, compared with placebo, pertuzumab prolonged investigator-assessed progression-free survival by 6.3 months (the same as that seen in the previous update) and prolonged overall survival by 16.3 months (up from 15.7 months in the previous update).

At 8 years, 37% of patients in the pertuzumab group were still alive, and 16% were still alive without progression.

“The combination of pertuzumab, trastuzumab, and docetaxel remains the standard of care for the first-line treatment of HER2-positive metastatic breast cancer, owing to its overall survival benefits and maintained long-term overall and cardiac safety,” Dr. Swain and coinvestigators concluded. “Prospective identification of patients who will be long-term responders to treatment is an area for future research.”

In an accompanying comment, Matteo Lambertini, MD, PhD, of IRCCS Ospedale Policlinico San Martino in Genova, Italy, and Ines Vaz-Luis, MD, of Institut Gustave Roussy in Villejuif, France, contended that these results, “which are also observed in real-world datasets, challenge the concept of HER2-positive metastatic breast cancer being an incurable disease and open the path to several interconnected clinical and research questions.”

Those questions include the optimal duration of anti-HER2 maintenance therapy in patients without disease progression, best strategies for combining this systemic therapy with local treatment to further improve survival, and new markers to better identify patients likely to be long-term responders, who might benefit from a curative approach, the authors elaborated. They noted that more than half of CLEOPATRA patients had de novo stage IV disease.

“The performance of the current standard pertuzumab-based first-line treatment in patients previously exposed to adjuvant or neoadjuvant anti-HER2 therapy remains to be clarified,” the authors wrote. “Results from several ongoing prospective cohort studies investigating real-world patterns of care and outcomes of patients with HER2-positive metastatic breast cancer will help to clarify this important issue and optimize treatment sequencing.”
 

Study details

The end-of-study analysis showed that median progression-free survival was 18.7 months with pertuzumab and 12.4 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.59-0.81). The 8-year landmark progression-free survival rate was 16% with the former and 10% with the latter.

The median overall survival was 57.1 months with pertuzumab and 40.8 months with placebo (HR, 0.69; 95% CI, 0.58-0.82). The 8-year landmark overall survival rate was 37% with the former and 23% with the latter.

A comparison of patients who did and did not achieve long-term response showed that, in both treatment groups, the former more often had tumors that were 3+ positive by HER2 immunohistochemistry and PIK3CA wild-type tumors. The leading grade 3 or 4 adverse event was neutropenia, seen in 49% of patients in the pertuzumab group and 46% of those in the placebo group. The rate of treatment-related death was 1% and 2%, respectively.

Since the last update, only two additional serious adverse events were reported: one case of heart failure and one case of symptomatic left ventricular systolic dysfunction in patients given pertuzumab.

The CLEOPATRA trial was funded by F. Hoffmann-La Roche and Genentech. Dr. Swain and coauthors disclosed relationships with these and other companies. Dr. Lambertini disclosed relationships with Roche, Theramex, and Takeda. Dr. Vaz-Luis disclosed relationships with AstraZeneca, Kephren, and Novartis.

SOURCE: Swain SM et al. Lancet Oncol. 2020 Mar 12. doi: 10.1016/S1470-2045(19)30863-0; Lambertini M et al. Lancet Oncol. 2020 Mar 12. doi: 10.1016/S1470-2045(20)30058-9.

Pertuzumab has a durable benefit in patients with metastatic HER2-positive breast cancer when added to trastuzumab and docetaxel as first-line therapy, with nearly 40% of patients achieving long-term survival, the CLEOPATRA end-of-study analysis shows.

The regimen, combining dual HER2 targeting with chemotherapy, became standard of care in this population as a result of its good efficacy and safety relative to placebo, first established in the phase 3, randomized trial 8 years ago (N Engl J Med. 2012;366:109-19).

Trial updates since then, most recently at a median follow-up of 50 months (N Engl J Med. 2015;372:724-34), have shown clear progression-free and overall survival benefits, with acceptable cardiac and other toxicity.

Investigators led by Sandra M. Swain, MD, of Georgetown University, Washington, performed a final analysis of data from the 808 patients in CLEOPATRA, now at a median follow-up of 99.9 months.

Results reported in The Lancet Oncology showed that, compared with placebo, pertuzumab prolonged investigator-assessed progression-free survival by 6.3 months (the same as that seen in the previous update) and prolonged overall survival by 16.3 months (up from 15.7 months in the previous update).

At 8 years, 37% of patients in the pertuzumab group were still alive, and 16% were still alive without progression.

“The combination of pertuzumab, trastuzumab, and docetaxel remains the standard of care for the first-line treatment of HER2-positive metastatic breast cancer, owing to its overall survival benefits and maintained long-term overall and cardiac safety,” Dr. Swain and coinvestigators concluded. “Prospective identification of patients who will be long-term responders to treatment is an area for future research.”

In an accompanying comment, Matteo Lambertini, MD, PhD, of IRCCS Ospedale Policlinico San Martino in Genova, Italy, and Ines Vaz-Luis, MD, of Institut Gustave Roussy in Villejuif, France, contended that these results, “which are also observed in real-world datasets, challenge the concept of HER2-positive metastatic breast cancer being an incurable disease and open the path to several interconnected clinical and research questions.”

Those questions include the optimal duration of anti-HER2 maintenance therapy in patients without disease progression, best strategies for combining this systemic therapy with local treatment to further improve survival, and new markers to better identify patients likely to be long-term responders, who might benefit from a curative approach, the authors elaborated. They noted that more than half of CLEOPATRA patients had de novo stage IV disease.

“The performance of the current standard pertuzumab-based first-line treatment in patients previously exposed to adjuvant or neoadjuvant anti-HER2 therapy remains to be clarified,” the authors wrote. “Results from several ongoing prospective cohort studies investigating real-world patterns of care and outcomes of patients with HER2-positive metastatic breast cancer will help to clarify this important issue and optimize treatment sequencing.”
 

Study details

The end-of-study analysis showed that median progression-free survival was 18.7 months with pertuzumab and 12.4 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.59-0.81). The 8-year landmark progression-free survival rate was 16% with the former and 10% with the latter.

The median overall survival was 57.1 months with pertuzumab and 40.8 months with placebo (HR, 0.69; 95% CI, 0.58-0.82). The 8-year landmark overall survival rate was 37% with the former and 23% with the latter.

A comparison of patients who did and did not achieve long-term response showed that, in both treatment groups, the former more often had tumors that were 3+ positive by HER2 immunohistochemistry and PIK3CA wild-type tumors. The leading grade 3 or 4 adverse event was neutropenia, seen in 49% of patients in the pertuzumab group and 46% of those in the placebo group. The rate of treatment-related death was 1% and 2%, respectively.

Since the last update, only two additional serious adverse events were reported: one case of heart failure and one case of symptomatic left ventricular systolic dysfunction in patients given pertuzumab.

The CLEOPATRA trial was funded by F. Hoffmann-La Roche and Genentech. Dr. Swain and coauthors disclosed relationships with these and other companies. Dr. Lambertini disclosed relationships with Roche, Theramex, and Takeda. Dr. Vaz-Luis disclosed relationships with AstraZeneca, Kephren, and Novartis.

SOURCE: Swain SM et al. Lancet Oncol. 2020 Mar 12. doi: 10.1016/S1470-2045(19)30863-0; Lambertini M et al. Lancet Oncol. 2020 Mar 12. doi: 10.1016/S1470-2045(20)30058-9.

The live attenuated zoster vaccine (Zostavax) does not provide adequate long-term protection in patients with rheumatoid arthritis (RA) starting tofacitinib, suggests the ORAL Sequel extension study.

Elsevier

The incidence of herpes zoster in patients with RA taking tofacitinib (Xeljanz), an oral Janus kinase inhibitor, is about double the rate seen with biologic disease-modifying antirheumatic drugs, noted the investigators, who were led by Kevin L. Winthrop, MD, professor of infectious diseases, ophthalmology, public health, and preventive medicine at Oregon Health & Science University, Portland. The American College of Rheumatology’s guideline for the treatment of RA recommends herpes zoster vaccination before patients aged 50 years or older initiate any of these agents.

The investigators studied 100 patients with RA from an index randomized, placebo-controlled trial of tofacitinib who started the long-term extension study 14 weeks after receiving the live attenuated zoster vaccine. All were given open-label tofacitinib, at 5 or 10 mg two times per day, along with background RA therapy as needed.

With a follow-up of 27 months, five patients (5%) developed herpes zoster, including two treated with the 5-mg dose and three treated with the 10-mg dose, according to results reported in Annals of the Rheumatic Diseases. Cases occurred between 218 and 741 days after vaccination.

Four of the patients had herpes zoster involving a single dermatome, while one had involvement of five dermatomes. All episodes were mild or moderate, and resolved with antiviral therapy.

Humoral and cell-mediated immunity to the varicella zoster virus were assessed with immunoglobulin G titer and an interferon-gamma enzyme-linked immunosorbent spot assay, respectively. Results showed that three of the patients developing herpes zoster had undetectable cell-mediated immunity to the virus at baseline and week 6 after vaccination. The other two patients had an adequate humoral and cell-mediated immune response to the vaccine, as assessed from changes from baseline, but had below-average immunoglobulin G titer at baseline and week 6.

“These results suggest that [live attenuated zoster vaccine] may not provide adequate long-term protection, as previously demonstrated in healthy individuals aged ≥60 years 3 years post-vaccination, in which [herpes zoster] risk was reduced by 51%,” Dr. Winthrop and colleagues wrote.

“While it is possible that [live attenuated zoster vaccine] booster vaccinations may improve vaccine efficacy, to date there is a lack of data on the use and timing of booster vaccinations, and no recommendations on the use of [live attenuated zoster vaccine] booster vaccinations currently exist,” they concluded. “This highlights the importance of evaluating the newly approved subunit non-live vaccine (Shingrix) in patients with RA receiving tofacitinib.”

The study was sponsored by Pfizer. Dr. Winthrop disclosed consulting for AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, and UCB and receiving grant/research support from Bristol-Myers Squibb. Two coauthors disclosed financial relationships with Pfizer and other pharmaceutical companies, and the other seven coauthors were employees and shareholders of Pfizer.

SOURCE: Winthrop KL et al. Ann Rheum Dis. 2020 Mar 11. doi: 10.1136/annrheumdis-2019-216566.

The live attenuated zoster vaccine (Zostavax) does not provide adequate long-term protection in patients with rheumatoid arthritis (RA) starting tofacitinib, suggests the ORAL Sequel extension study.

Elsevier

The incidence of herpes zoster in patients with RA taking tofacitinib (Xeljanz), an oral Janus kinase inhibitor, is about double the rate seen with biologic disease-modifying antirheumatic drugs, noted the investigators, who were led by Kevin L. Winthrop, MD, professor of infectious diseases, ophthalmology, public health, and preventive medicine at Oregon Health & Science University, Portland. The American College of Rheumatology’s guideline for the treatment of RA recommends herpes zoster vaccination before patients aged 50 years or older initiate any of these agents.

The investigators studied 100 patients with RA from an index randomized, placebo-controlled trial of tofacitinib who started the long-term extension study 14 weeks after receiving the live attenuated zoster vaccine. All were given open-label tofacitinib, at 5 or 10 mg two times per day, along with background RA therapy as needed.

With a follow-up of 27 months, five patients (5%) developed herpes zoster, including two treated with the 5-mg dose and three treated with the 10-mg dose, according to results reported in Annals of the Rheumatic Diseases. Cases occurred between 218 and 741 days after vaccination.

Four of the patients had herpes zoster involving a single dermatome, while one had involvement of five dermatomes. All episodes were mild or moderate, and resolved with antiviral therapy.

Humoral and cell-mediated immunity to the varicella zoster virus were assessed with immunoglobulin G titer and an interferon-gamma enzyme-linked immunosorbent spot assay, respectively. Results showed that three of the patients developing herpes zoster had undetectable cell-mediated immunity to the virus at baseline and week 6 after vaccination. The other two patients had an adequate humoral and cell-mediated immune response to the vaccine, as assessed from changes from baseline, but had below-average immunoglobulin G titer at baseline and week 6.

“These results suggest that [live attenuated zoster vaccine] may not provide adequate long-term protection, as previously demonstrated in healthy individuals aged ≥60 years 3 years post-vaccination, in which [herpes zoster] risk was reduced by 51%,” Dr. Winthrop and colleagues wrote.

“While it is possible that [live attenuated zoster vaccine] booster vaccinations may improve vaccine efficacy, to date there is a lack of data on the use and timing of booster vaccinations, and no recommendations on the use of [live attenuated zoster vaccine] booster vaccinations currently exist,” they concluded. “This highlights the importance of evaluating the newly approved subunit non-live vaccine (Shingrix) in patients with RA receiving tofacitinib.”

The study was sponsored by Pfizer. Dr. Winthrop disclosed consulting for AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, and UCB and receiving grant/research support from Bristol-Myers Squibb. Two coauthors disclosed financial relationships with Pfizer and other pharmaceutical companies, and the other seven coauthors were employees and shareholders of Pfizer.

SOURCE: Winthrop KL et al. Ann Rheum Dis. 2020 Mar 11. doi: 10.1136/annrheumdis-2019-216566.

The live attenuated zoster vaccine (Zostavax) does not provide adequate long-term protection in patients with rheumatoid arthritis (RA) starting tofacitinib, suggests the ORAL Sequel extension study.

Elsevier

The incidence of herpes zoster in patients with RA taking tofacitinib (Xeljanz), an oral Janus kinase inhibitor, is about double the rate seen with biologic disease-modifying antirheumatic drugs, noted the investigators, who were led by Kevin L. Winthrop, MD, professor of infectious diseases, ophthalmology, public health, and preventive medicine at Oregon Health & Science University, Portland. The American College of Rheumatology’s guideline for the treatment of RA recommends herpes zoster vaccination before patients aged 50 years or older initiate any of these agents.

The investigators studied 100 patients with RA from an index randomized, placebo-controlled trial of tofacitinib who started the long-term extension study 14 weeks after receiving the live attenuated zoster vaccine. All were given open-label tofacitinib, at 5 or 10 mg two times per day, along with background RA therapy as needed.

With a follow-up of 27 months, five patients (5%) developed herpes zoster, including two treated with the 5-mg dose and three treated with the 10-mg dose, according to results reported in Annals of the Rheumatic Diseases. Cases occurred between 218 and 741 days after vaccination.

Four of the patients had herpes zoster involving a single dermatome, while one had involvement of five dermatomes. All episodes were mild or moderate, and resolved with antiviral therapy.

Humoral and cell-mediated immunity to the varicella zoster virus were assessed with immunoglobulin G titer and an interferon-gamma enzyme-linked immunosorbent spot assay, respectively. Results showed that three of the patients developing herpes zoster had undetectable cell-mediated immunity to the virus at baseline and week 6 after vaccination. The other two patients had an adequate humoral and cell-mediated immune response to the vaccine, as assessed from changes from baseline, but had below-average immunoglobulin G titer at baseline and week 6.

“These results suggest that [live attenuated zoster vaccine] may not provide adequate long-term protection, as previously demonstrated in healthy individuals aged ≥60 years 3 years post-vaccination, in which [herpes zoster] risk was reduced by 51%,” Dr. Winthrop and colleagues wrote.

“While it is possible that [live attenuated zoster vaccine] booster vaccinations may improve vaccine efficacy, to date there is a lack of data on the use and timing of booster vaccinations, and no recommendations on the use of [live attenuated zoster vaccine] booster vaccinations currently exist,” they concluded. “This highlights the importance of evaluating the newly approved subunit non-live vaccine (Shingrix) in patients with RA receiving tofacitinib.”

The study was sponsored by Pfizer. Dr. Winthrop disclosed consulting for AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, and UCB and receiving grant/research support from Bristol-Myers Squibb. Two coauthors disclosed financial relationships with Pfizer and other pharmaceutical companies, and the other seven coauthors were employees and shareholders of Pfizer.

SOURCE: Winthrop KL et al. Ann Rheum Dis. 2020 Mar 11. doi: 10.1136/annrheumdis-2019-216566.

Skin cancer detection does not improve when patients use a dermatoscope for smartphones to capture and send photos of lesions for diagnosis, according to the Australian SKIN Project trial.

“Mobile health applications are increasingly used in cancer prevention and early detection but rarely tested stringently for their value with regard to patient care,” noted trial investigators, who were led by Monika Janda, PhD, of the University of Queensland in Brisbane, Australia. The trial was published in Lancet Digital Health.

The investigators studied 234 adults at high risk for skin cancer, asking them to perform whole-body skin self-exams in their homes at baseline, 1 month, and 2 months.

Half of patients were randomized to perform standard naked-eye exams, note suspicious lesions on a body chart, and submit the chart by email. The other half were randomized to supplement their exams with mobile dermoscopy, and they were provided with a dermatoscope (FotoFinder) that interfaces with smartphones to capture and submit photos of suspicious lesions to a dermatologist for telediagnosis.

Both groups received Web-based instructions on how to complete whole-body skin self-exams and were examined in person within 3 months of their last self-exam to provide a reference standard.

In comparing the two approaches for early detection of skin cancer, the investigators determined that teledermoscopy-enhanced exams would have to show 20% greater sensitivity to establish their superiority.

The median number of lesions submitted was six per person in both the group using adjunctive teledermoscopy and the group performing only naked-eye exams.

At the lesion level, teledermoscopy-enhanced exams had lower sensitivity than naked-eye exams in detecting suspected skin cancers or precursor lesions (75% vs. 88%; P = .04) and similar specificity (87% vs. 89%; P = .42). At the patient level, the two approaches had statistically indistinguishable sensitivity (87% vs. 97%; P = .26) and specificity (95% vs. 96%; P = .96).

At the same time, telediagnosis showed good overall diagnostic concordance with in-person clinical skin examination (88%).

“For the early detection of skin cancer, naked-eye skin self-examination should continue to be recommended by cancer agencies,” Dr. Janda and colleagues concluded. “Further improvements to the instructions for participants on the relevance of nonpigmented skin lesions, training for partners, and the integration of automatic algorithms that rule out clearly benign skin lesions at the time of photographing might increase sensitivity of teledermoscopy in the future.”

This trial was funded by the National Health and Medical Research Council. The authors disclosed relationships with e-derm-consult, SciBase, Canfield Scientific, and other companies.

SOURCE: Janda M et al. Lancet Digit Health. 2020 March; 2(3):e129-e137.

Skin cancer detection does not improve when patients use a dermatoscope for smartphones to capture and send photos of lesions for diagnosis, according to the Australian SKIN Project trial.

“Mobile health applications are increasingly used in cancer prevention and early detection but rarely tested stringently for their value with regard to patient care,” noted trial investigators, who were led by Monika Janda, PhD, of the University of Queensland in Brisbane, Australia. The trial was published in Lancet Digital Health.

The investigators studied 234 adults at high risk for skin cancer, asking them to perform whole-body skin self-exams in their homes at baseline, 1 month, and 2 months.

Half of patients were randomized to perform standard naked-eye exams, note suspicious lesions on a body chart, and submit the chart by email. The other half were randomized to supplement their exams with mobile dermoscopy, and they were provided with a dermatoscope (FotoFinder) that interfaces with smartphones to capture and submit photos of suspicious lesions to a dermatologist for telediagnosis.

Both groups received Web-based instructions on how to complete whole-body skin self-exams and were examined in person within 3 months of their last self-exam to provide a reference standard.

In comparing the two approaches for early detection of skin cancer, the investigators determined that teledermoscopy-enhanced exams would have to show 20% greater sensitivity to establish their superiority.

The median number of lesions submitted was six per person in both the group using adjunctive teledermoscopy and the group performing only naked-eye exams.

At the lesion level, teledermoscopy-enhanced exams had lower sensitivity than naked-eye exams in detecting suspected skin cancers or precursor lesions (75% vs. 88%; P = .04) and similar specificity (87% vs. 89%; P = .42). At the patient level, the two approaches had statistically indistinguishable sensitivity (87% vs. 97%; P = .26) and specificity (95% vs. 96%; P = .96).

At the same time, telediagnosis showed good overall diagnostic concordance with in-person clinical skin examination (88%).

“For the early detection of skin cancer, naked-eye skin self-examination should continue to be recommended by cancer agencies,” Dr. Janda and colleagues concluded. “Further improvements to the instructions for participants on the relevance of nonpigmented skin lesions, training for partners, and the integration of automatic algorithms that rule out clearly benign skin lesions at the time of photographing might increase sensitivity of teledermoscopy in the future.”

This trial was funded by the National Health and Medical Research Council. The authors disclosed relationships with e-derm-consult, SciBase, Canfield Scientific, and other companies.

SOURCE: Janda M et al. Lancet Digit Health. 2020 March; 2(3):e129-e137.

Skin cancer detection does not improve when patients use a dermatoscope for smartphones to capture and send photos of lesions for diagnosis, according to the Australian SKIN Project trial.

“Mobile health applications are increasingly used in cancer prevention and early detection but rarely tested stringently for their value with regard to patient care,” noted trial investigators, who were led by Monika Janda, PhD, of the University of Queensland in Brisbane, Australia. The trial was published in Lancet Digital Health.

The investigators studied 234 adults at high risk for skin cancer, asking them to perform whole-body skin self-exams in their homes at baseline, 1 month, and 2 months.

Half of patients were randomized to perform standard naked-eye exams, note suspicious lesions on a body chart, and submit the chart by email. The other half were randomized to supplement their exams with mobile dermoscopy, and they were provided with a dermatoscope (FotoFinder) that interfaces with smartphones to capture and submit photos of suspicious lesions to a dermatologist for telediagnosis.

Both groups received Web-based instructions on how to complete whole-body skin self-exams and were examined in person within 3 months of their last self-exam to provide a reference standard.

In comparing the two approaches for early detection of skin cancer, the investigators determined that teledermoscopy-enhanced exams would have to show 20% greater sensitivity to establish their superiority.

The median number of lesions submitted was six per person in both the group using adjunctive teledermoscopy and the group performing only naked-eye exams.

At the lesion level, teledermoscopy-enhanced exams had lower sensitivity than naked-eye exams in detecting suspected skin cancers or precursor lesions (75% vs. 88%; P = .04) and similar specificity (87% vs. 89%; P = .42). At the patient level, the two approaches had statistically indistinguishable sensitivity (87% vs. 97%; P = .26) and specificity (95% vs. 96%; P = .96).

At the same time, telediagnosis showed good overall diagnostic concordance with in-person clinical skin examination (88%).

“For the early detection of skin cancer, naked-eye skin self-examination should continue to be recommended by cancer agencies,” Dr. Janda and colleagues concluded. “Further improvements to the instructions for participants on the relevance of nonpigmented skin lesions, training for partners, and the integration of automatic algorithms that rule out clearly benign skin lesions at the time of photographing might increase sensitivity of teledermoscopy in the future.”

This trial was funded by the National Health and Medical Research Council. The authors disclosed relationships with e-derm-consult, SciBase, Canfield Scientific, and other companies.

SOURCE: Janda M et al. Lancet Digit Health. 2020 March; 2(3):e129-e137.

Eye and vision problems are highly prevalent among patients with Parkinson’s disease and often severe enough to interfere with daily activities, according to the results of a multicenter, cross-sectional cohort study.

“Ophthalmologic symptoms are underreported by patients with Parkinson’s disease and often overlooked by their treating physicians,” noted the investigators, who were led by Carlijn D.J.M. Borm, MD, Parkinson Centre Nijmegen (the Netherlands), Department of Neurology, Donders Institute for Brain, Cognition and Behaviour at Radboud University Medical Centre. “Importantly, intact vision is especially vital for patients with Parkinson’s disease to compensate (through visual guidance) for their common loss of motor automaticity that is caused by basal ganglia dysfunction.”

The investigators studied 848 patients with Parkinson’s disease in the Netherlands and Austria who were recruited by e-mail or in outpatient clinics and 250 age-matched healthy controls drawn from partners and acquaintances, comparing the groups on symptoms assessed with the Visual Impairment in Parkinson’s Disease Questionnaire (VIPD-Q).

Results reported in Neurology showed that 82% of patients with Parkinson’s disease reported at least one ophthalmologic symptom, compared with 48% of age-matched healthy controls (P < .001). Symptoms related to the ocular surface – blurry near vision, a burning or gritty sensation, mucus or particles, and watering of the eyes – were the most common.

Moreover, 68% of patients reported having ophthalmologic symptoms that interfered with daily activities, compared with 35% of healthy controls (P < .001).

The study’s findings suggest “that either Parkinson’s disease itself or its treatment has an effect on ophthalmologic functions beyond the normal aging process,” Dr. Borm and coinvestigators wrote. “The high prevalence of ophthalmologic symptoms and their effect on daily life is striking, and emphasizes the need to address this subject in both research and clinical practice.”

“Patients who report ophthalmologic symptoms need a referral for further evaluation. For those patients who do not volunteer problems themselves, a screening questionnaire such as the VIPD-Q may help with identifying ophthalmologic symptoms in patients with Parkinson’s disease that might otherwise be missed, thereby enabling timely referral and treatment,” they noted.
 

Study details

The study participants were 70 years old, on average, and the patients with Parkinson’s disease had had the disease for a median duration of 7 years. Compared with the healthy control group, the patient group more often reported that they used visual aids (95% vs. 88%; P = .001) and had visited an ophthalmologist (35% vs. 19%; P < .001). The median score on the VIPD-Q, out of a possible 51 points, was 10 among the patients with Parkinson’s disease, compared with 2 among the healthy controls (P < .001).

Patients most commonly reported symptoms related to the ocular surface (63% vs. 24% among controls; P < .001). But they also often reported symptoms in the intraocular domain (54% vs. 25%; P < .001), the oculomotor domain (44% vs. 10%; P < .001), and the optic nerve domain (44% vs. 19%; P < .001). Fully 22% of the patients reported visual hallucinations, compared with just 2% of the healthy controls (P < .001).

As VIPD-Q score increased, so did the likelihood of falls (odds ratio, 1.043; P < .001). In addition, patients with Parkinson’s disease more often reported that ophthalmologic symptoms had a moderate or severe impact on their quality of life (53% vs. 16%; P < .001).

Dr. Borm disclosed no relevant conflicts of interest. The study was funded by the Stichting Parkinson Fonds.
 

Awareness is key to spotting these treatable symptoms

“This study confirms a lot of what we already knew about Parkinson’s disease, but it gives more numbers to it and also the patient’s perspective rather than the doctor’s perspective,” Andrew G. Lee, MD, commented in an interview. “We know that patients with Parkinson’s disease have a lot of ophthalmologic symptoms – probably more than we recognize or ask about in the clinic – and their symptoms predominantly are out of proportion to what we see on exam,” said Dr. Lee, who is chairman of the Department of Ophthalmology at Blanton Eye Institute, Houston Methodist Hospital.

In fact, patients may have normal acuity, normal visual fields, and a normal structural eye exam, yet still report vision problems because of the central neurodegeneration occurring, he noted. “Ophthalmologists cannot rely on just the eye exam when examining patients with Parkinson’s disease. They have to take symptoms into consideration. It’s really important to be aware of how brain disease can affect the eyes symptom-wise, even though the eye exam is normal.”

Administering the questionnaire used in the study is not very difficult but is somewhat time consuming, so most ophthalmologists and neurologists are unlikely to use it, according to Dr. Lee. But knowing common symptoms and asking about them can ensure they are promptly recognized, the first step in addressing them.

“None of the visual complaints in patients with Parkinson’s disease are curable because Parkinson’s disease is not curable and the disease is the underlying major etiology for the problems. However, all of the symptoms have treatments,” he said.

For example, dry eye, caused by decreased blinking, can be treated with drops. Convergence insufficiency, which generates double vision when focusing on nearby objects, can be managed with prisms, exercises, and if needed, eye muscle surgery. Impaired eye movement is best treated with different sets of glasses specific to tasks, such as one pair for reading and one pair for distance. And visual hallucinations can be addressed with changes to existing medications or new medication, or simple reassurance that the hallucinations aren’t harmful.

“It’s important that this kind of study increases awareness in the medical community,” concluded Dr. Lee, who disclosed no relevant conflicts of interest. “The take-home messages are that eye doctors know that these are real complaints, that the eye exam is not going to give the answer, and that all of the symptoms have treatments even though there is no cure.”

SOURCE: Borm CDJM et al. Neurology. 2020 Mar 11. doi: 10.1212/WNL.0000000000009214.

Eye and vision problems are highly prevalent among patients with Parkinson’s disease and often severe enough to interfere with daily activities, according to the results of a multicenter, cross-sectional cohort study.

“Ophthalmologic symptoms are underreported by patients with Parkinson’s disease and often overlooked by their treating physicians,” noted the investigators, who were led by Carlijn D.J.M. Borm, MD, Parkinson Centre Nijmegen (the Netherlands), Department of Neurology, Donders Institute for Brain, Cognition and Behaviour at Radboud University Medical Centre. “Importantly, intact vision is especially vital for patients with Parkinson’s disease to compensate (through visual guidance) for their common loss of motor automaticity that is caused by basal ganglia dysfunction.”

The investigators studied 848 patients with Parkinson’s disease in the Netherlands and Austria who were recruited by e-mail or in outpatient clinics and 250 age-matched healthy controls drawn from partners and acquaintances, comparing the groups on symptoms assessed with the Visual Impairment in Parkinson’s Disease Questionnaire (VIPD-Q).

Results reported in Neurology showed that 82% of patients with Parkinson’s disease reported at least one ophthalmologic symptom, compared with 48% of age-matched healthy controls (P < .001). Symptoms related to the ocular surface – blurry near vision, a burning or gritty sensation, mucus or particles, and watering of the eyes – were the most common.

Moreover, 68% of patients reported having ophthalmologic symptoms that interfered with daily activities, compared with 35% of healthy controls (P < .001).

The study’s findings suggest “that either Parkinson’s disease itself or its treatment has an effect on ophthalmologic functions beyond the normal aging process,” Dr. Borm and coinvestigators wrote. “The high prevalence of ophthalmologic symptoms and their effect on daily life is striking, and emphasizes the need to address this subject in both research and clinical practice.”

“Patients who report ophthalmologic symptoms need a referral for further evaluation. For those patients who do not volunteer problems themselves, a screening questionnaire such as the VIPD-Q may help with identifying ophthalmologic symptoms in patients with Parkinson’s disease that might otherwise be missed, thereby enabling timely referral and treatment,” they noted.
 

Study details

The study participants were 70 years old, on average, and the patients with Parkinson’s disease had had the disease for a median duration of 7 years. Compared with the healthy control group, the patient group more often reported that they used visual aids (95% vs. 88%; P = .001) and had visited an ophthalmologist (35% vs. 19%; P < .001). The median score on the VIPD-Q, out of a possible 51 points, was 10 among the patients with Parkinson’s disease, compared with 2 among the healthy controls (P < .001).

Patients most commonly reported symptoms related to the ocular surface (63% vs. 24% among controls; P < .001). But they also often reported symptoms in the intraocular domain (54% vs. 25%; P < .001), the oculomotor domain (44% vs. 10%; P < .001), and the optic nerve domain (44% vs. 19%; P < .001). Fully 22% of the patients reported visual hallucinations, compared with just 2% of the healthy controls (P < .001).

As VIPD-Q score increased, so did the likelihood of falls (odds ratio, 1.043; P < .001). In addition, patients with Parkinson’s disease more often reported that ophthalmologic symptoms had a moderate or severe impact on their quality of life (53% vs. 16%; P < .001).

Dr. Borm disclosed no relevant conflicts of interest. The study was funded by the Stichting Parkinson Fonds.
 

Awareness is key to spotting these treatable symptoms

“This study confirms a lot of what we already knew about Parkinson’s disease, but it gives more numbers to it and also the patient’s perspective rather than the doctor’s perspective,” Andrew G. Lee, MD, commented in an interview. “We know that patients with Parkinson’s disease have a lot of ophthalmologic symptoms – probably more than we recognize or ask about in the clinic – and their symptoms predominantly are out of proportion to what we see on exam,” said Dr. Lee, who is chairman of the Department of Ophthalmology at Blanton Eye Institute, Houston Methodist Hospital.

In fact, patients may have normal acuity, normal visual fields, and a normal structural eye exam, yet still report vision problems because of the central neurodegeneration occurring, he noted. “Ophthalmologists cannot rely on just the eye exam when examining patients with Parkinson’s disease. They have to take symptoms into consideration. It’s really important to be aware of how brain disease can affect the eyes symptom-wise, even though the eye exam is normal.”

Administering the questionnaire used in the study is not very difficult but is somewhat time consuming, so most ophthalmologists and neurologists are unlikely to use it, according to Dr. Lee. But knowing common symptoms and asking about them can ensure they are promptly recognized, the first step in addressing them.

“None of the visual complaints in patients with Parkinson’s disease are curable because Parkinson’s disease is not curable and the disease is the underlying major etiology for the problems. However, all of the symptoms have treatments,” he said.

For example, dry eye, caused by decreased blinking, can be treated with drops. Convergence insufficiency, which generates double vision when focusing on nearby objects, can be managed with prisms, exercises, and if needed, eye muscle surgery. Impaired eye movement is best treated with different sets of glasses specific to tasks, such as one pair for reading and one pair for distance. And visual hallucinations can be addressed with changes to existing medications or new medication, or simple reassurance that the hallucinations aren’t harmful.

“It’s important that this kind of study increases awareness in the medical community,” concluded Dr. Lee, who disclosed no relevant conflicts of interest. “The take-home messages are that eye doctors know that these are real complaints, that the eye exam is not going to give the answer, and that all of the symptoms have treatments even though there is no cure.”

SOURCE: Borm CDJM et al. Neurology. 2020 Mar 11. doi: 10.1212/WNL.0000000000009214.

Eye and vision problems are highly prevalent among patients with Parkinson’s disease and often severe enough to interfere with daily activities, according to the results of a multicenter, cross-sectional cohort study.

“Ophthalmologic symptoms are underreported by patients with Parkinson’s disease and often overlooked by their treating physicians,” noted the investigators, who were led by Carlijn D.J.M. Borm, MD, Parkinson Centre Nijmegen (the Netherlands), Department of Neurology, Donders Institute for Brain, Cognition and Behaviour at Radboud University Medical Centre. “Importantly, intact vision is especially vital for patients with Parkinson’s disease to compensate (through visual guidance) for their common loss of motor automaticity that is caused by basal ganglia dysfunction.”

The investigators studied 848 patients with Parkinson’s disease in the Netherlands and Austria who were recruited by e-mail or in outpatient clinics and 250 age-matched healthy controls drawn from partners and acquaintances, comparing the groups on symptoms assessed with the Visual Impairment in Parkinson’s Disease Questionnaire (VIPD-Q).

Results reported in Neurology showed that 82% of patients with Parkinson’s disease reported at least one ophthalmologic symptom, compared with 48% of age-matched healthy controls (P < .001). Symptoms related to the ocular surface – blurry near vision, a burning or gritty sensation, mucus or particles, and watering of the eyes – were the most common.

Moreover, 68% of patients reported having ophthalmologic symptoms that interfered with daily activities, compared with 35% of healthy controls (P < .001).

The study’s findings suggest “that either Parkinson’s disease itself or its treatment has an effect on ophthalmologic functions beyond the normal aging process,” Dr. Borm and coinvestigators wrote. “The high prevalence of ophthalmologic symptoms and their effect on daily life is striking, and emphasizes the need to address this subject in both research and clinical practice.”

“Patients who report ophthalmologic symptoms need a referral for further evaluation. For those patients who do not volunteer problems themselves, a screening questionnaire such as the VIPD-Q may help with identifying ophthalmologic symptoms in patients with Parkinson’s disease that might otherwise be missed, thereby enabling timely referral and treatment,” they noted.
 

Study details

The study participants were 70 years old, on average, and the patients with Parkinson’s disease had had the disease for a median duration of 7 years. Compared with the healthy control group, the patient group more often reported that they used visual aids (95% vs. 88%; P = .001) and had visited an ophthalmologist (35% vs. 19%; P < .001). The median score on the VIPD-Q, out of a possible 51 points, was 10 among the patients with Parkinson’s disease, compared with 2 among the healthy controls (P < .001).

Patients most commonly reported symptoms related to the ocular surface (63% vs. 24% among controls; P < .001). But they also often reported symptoms in the intraocular domain (54% vs. 25%; P < .001), the oculomotor domain (44% vs. 10%; P < .001), and the optic nerve domain (44% vs. 19%; P < .001). Fully 22% of the patients reported visual hallucinations, compared with just 2% of the healthy controls (P < .001).

As VIPD-Q score increased, so did the likelihood of falls (odds ratio, 1.043; P < .001). In addition, patients with Parkinson’s disease more often reported that ophthalmologic symptoms had a moderate or severe impact on their quality of life (53% vs. 16%; P < .001).

Dr. Borm disclosed no relevant conflicts of interest. The study was funded by the Stichting Parkinson Fonds.
 

Awareness is key to spotting these treatable symptoms

“This study confirms a lot of what we already knew about Parkinson’s disease, but it gives more numbers to it and also the patient’s perspective rather than the doctor’s perspective,” Andrew G. Lee, MD, commented in an interview. “We know that patients with Parkinson’s disease have a lot of ophthalmologic symptoms – probably more than we recognize or ask about in the clinic – and their symptoms predominantly are out of proportion to what we see on exam,” said Dr. Lee, who is chairman of the Department of Ophthalmology at Blanton Eye Institute, Houston Methodist Hospital.

In fact, patients may have normal acuity, normal visual fields, and a normal structural eye exam, yet still report vision problems because of the central neurodegeneration occurring, he noted. “Ophthalmologists cannot rely on just the eye exam when examining patients with Parkinson’s disease. They have to take symptoms into consideration. It’s really important to be aware of how brain disease can affect the eyes symptom-wise, even though the eye exam is normal.”

Administering the questionnaire used in the study is not very difficult but is somewhat time consuming, so most ophthalmologists and neurologists are unlikely to use it, according to Dr. Lee. But knowing common symptoms and asking about them can ensure they are promptly recognized, the first step in addressing them.

“None of the visual complaints in patients with Parkinson’s disease are curable because Parkinson’s disease is not curable and the disease is the underlying major etiology for the problems. However, all of the symptoms have treatments,” he said.

For example, dry eye, caused by decreased blinking, can be treated with drops. Convergence insufficiency, which generates double vision when focusing on nearby objects, can be managed with prisms, exercises, and if needed, eye muscle surgery. Impaired eye movement is best treated with different sets of glasses specific to tasks, such as one pair for reading and one pair for distance. And visual hallucinations can be addressed with changes to existing medications or new medication, or simple reassurance that the hallucinations aren’t harmful.

“It’s important that this kind of study increases awareness in the medical community,” concluded Dr. Lee, who disclosed no relevant conflicts of interest. “The take-home messages are that eye doctors know that these are real complaints, that the eye exam is not going to give the answer, and that all of the symptoms have treatments even though there is no cure.”

SOURCE: Borm CDJM et al. Neurology. 2020 Mar 11. doi: 10.1212/WNL.0000000000009214.

Adjuvant platinum-based chemotherapy has good efficacy and acceptable safety in patients with locally advanced upper tract urothelial carcinoma (UTUC) and should therefore be a new standard of care, according to investigators from the POUT trial.

The risk of disease-free survival events was reduced by more than half for patients who started platinum-based chemotherapy within 90 days after nephroureterectomy, compared with counterparts who simply received surveillance. The treatment was generally well tolerated, with adverse events as expected for this regimen and only a transient impact on quality of life.

Alison Birtle, MD, of Lancashire Teaching Hospitals National Health Services Foundation Trust in Preston, England, and colleagues conducted this trial and reported the results in the Lancet.

“Urothelial carcinomas of the upper urinary tract … are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder,” the investigators wrote. “No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent.”

With this in mind, the investigators conducted the phase 3 POUT trial (NCT01993979), which is the largest trial to report outcomes exclusively in patients with UTUC. The trial included 261 patients with UTUC (transitional cell carcinoma of the ureter or renal pelvis) that was locally advanced at either pT2-T4 pN0-N3 M0 stage or pTany N1-3 M0 stage.

Patients were randomized to chemotherapy (n = 132) or surveillance (n = 129). Patients in the chemotherapy arm received four 21-day cycles of gemcitabine plus cisplatin or, when renal function was impaired, carboplatin.

With a median follow-up of 30.3 months, patients who received chemotherapy had a lower risk of disease recurrence or death, relative to counterparts who received only surveillance (hazard ratio, 0.45; P = .0001), with similar benefit across subgroups. The estimated 3-year disease-free survival rate was 71% in the chemotherapy arm and 46% in the surveillance arm. The median disease-free survival was 29.8 months and not reached, respectively.

The chemotherapy group also had a lower risk of metastasis or death when compared with the surveillance group (HR, 0.48; P = .0007). The 3-year event-free rates were 71% and 53%, respectively. Overall survival data are not yet mature.

“We acknowledge that disease-free survival is not regarded as a fully validated surrogate of overall survival after nephroureterectomy for UTUC,” the investigators wrote. “However, in a rare disease such as UTUC, a suitably powered trial with overall survival as the primary endpoint was not judged feasible. Although mature survival data (as a secondary endpoint) are not yet available, the large improvement in disease-free survival we noted for the primary endpoint, together with improved metastasis-free survival recorded as a secondary endpoint, strongly suggest that patients have better outcomes with chemotherapy than without.”

The incidence of acute grade 3 or worse treatment-emergent adverse events was 44% in the chemotherapy arm and 4% in the surveillance arm (P less than .0001). Quality of life was worse for the chemotherapy arm at 3 months (P = .0028), but that was no longer the case at 12 months (P = .20). There were no treatment-related deaths.

“[A]djuvant platinum-based chemotherapy should be adopted as a new standard of care for patients with locally advanced UTUC for whom systemic chemotherapy is not contraindicated,” the investigators recommended. “This regimen should be routinely considered for all patients in this population, and future studies should focus on combinations with novel agents in the adjuvant setting, which might further improve the prognosis for locally advanced UTUC.”

The trial was funded by Cancer Research UK. The authors disclosed relationships with numerous pharmaceutical companies.

SOURCE: Birtle A et al. Lancet. 2020 Mar 5. doi: 10.1016/S0140-6736(20)30415-3.

Adjuvant platinum-based chemotherapy has good efficacy and acceptable safety in patients with locally advanced upper tract urothelial carcinoma (UTUC) and should therefore be a new standard of care, according to investigators from the POUT trial.

The risk of disease-free survival events was reduced by more than half for patients who started platinum-based chemotherapy within 90 days after nephroureterectomy, compared with counterparts who simply received surveillance. The treatment was generally well tolerated, with adverse events as expected for this regimen and only a transient impact on quality of life.

Alison Birtle, MD, of Lancashire Teaching Hospitals National Health Services Foundation Trust in Preston, England, and colleagues conducted this trial and reported the results in the Lancet.

“Urothelial carcinomas of the upper urinary tract … are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder,” the investigators wrote. “No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent.”

With this in mind, the investigators conducted the phase 3 POUT trial (NCT01993979), which is the largest trial to report outcomes exclusively in patients with UTUC. The trial included 261 patients with UTUC (transitional cell carcinoma of the ureter or renal pelvis) that was locally advanced at either pT2-T4 pN0-N3 M0 stage or pTany N1-3 M0 stage.

Patients were randomized to chemotherapy (n = 132) or surveillance (n = 129). Patients in the chemotherapy arm received four 21-day cycles of gemcitabine plus cisplatin or, when renal function was impaired, carboplatin.

With a median follow-up of 30.3 months, patients who received chemotherapy had a lower risk of disease recurrence or death, relative to counterparts who received only surveillance (hazard ratio, 0.45; P = .0001), with similar benefit across subgroups. The estimated 3-year disease-free survival rate was 71% in the chemotherapy arm and 46% in the surveillance arm. The median disease-free survival was 29.8 months and not reached, respectively.

The chemotherapy group also had a lower risk of metastasis or death when compared with the surveillance group (HR, 0.48; P = .0007). The 3-year event-free rates were 71% and 53%, respectively. Overall survival data are not yet mature.

“We acknowledge that disease-free survival is not regarded as a fully validated surrogate of overall survival after nephroureterectomy for UTUC,” the investigators wrote. “However, in a rare disease such as UTUC, a suitably powered trial with overall survival as the primary endpoint was not judged feasible. Although mature survival data (as a secondary endpoint) are not yet available, the large improvement in disease-free survival we noted for the primary endpoint, together with improved metastasis-free survival recorded as a secondary endpoint, strongly suggest that patients have better outcomes with chemotherapy than without.”

The incidence of acute grade 3 or worse treatment-emergent adverse events was 44% in the chemotherapy arm and 4% in the surveillance arm (P less than .0001). Quality of life was worse for the chemotherapy arm at 3 months (P = .0028), but that was no longer the case at 12 months (P = .20). There were no treatment-related deaths.

“[A]djuvant platinum-based chemotherapy should be adopted as a new standard of care for patients with locally advanced UTUC for whom systemic chemotherapy is not contraindicated,” the investigators recommended. “This regimen should be routinely considered for all patients in this population, and future studies should focus on combinations with novel agents in the adjuvant setting, which might further improve the prognosis for locally advanced UTUC.”

The trial was funded by Cancer Research UK. The authors disclosed relationships with numerous pharmaceutical companies.

SOURCE: Birtle A et al. Lancet. 2020 Mar 5. doi: 10.1016/S0140-6736(20)30415-3.

Adjuvant platinum-based chemotherapy has good efficacy and acceptable safety in patients with locally advanced upper tract urothelial carcinoma (UTUC) and should therefore be a new standard of care, according to investigators from the POUT trial.

The risk of disease-free survival events was reduced by more than half for patients who started platinum-based chemotherapy within 90 days after nephroureterectomy, compared with counterparts who simply received surveillance. The treatment was generally well tolerated, with adverse events as expected for this regimen and only a transient impact on quality of life.

Alison Birtle, MD, of Lancashire Teaching Hospitals National Health Services Foundation Trust in Preston, England, and colleagues conducted this trial and reported the results in the Lancet.

“Urothelial carcinomas of the upper urinary tract … are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder,” the investigators wrote. “No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent.”

With this in mind, the investigators conducted the phase 3 POUT trial (NCT01993979), which is the largest trial to report outcomes exclusively in patients with UTUC. The trial included 261 patients with UTUC (transitional cell carcinoma of the ureter or renal pelvis) that was locally advanced at either pT2-T4 pN0-N3 M0 stage or pTany N1-3 M0 stage.

Patients were randomized to chemotherapy (n = 132) or surveillance (n = 129). Patients in the chemotherapy arm received four 21-day cycles of gemcitabine plus cisplatin or, when renal function was impaired, carboplatin.

With a median follow-up of 30.3 months, patients who received chemotherapy had a lower risk of disease recurrence or death, relative to counterparts who received only surveillance (hazard ratio, 0.45; P = .0001), with similar benefit across subgroups. The estimated 3-year disease-free survival rate was 71% in the chemotherapy arm and 46% in the surveillance arm. The median disease-free survival was 29.8 months and not reached, respectively.

The chemotherapy group also had a lower risk of metastasis or death when compared with the surveillance group (HR, 0.48; P = .0007). The 3-year event-free rates were 71% and 53%, respectively. Overall survival data are not yet mature.

“We acknowledge that disease-free survival is not regarded as a fully validated surrogate of overall survival after nephroureterectomy for UTUC,” the investigators wrote. “However, in a rare disease such as UTUC, a suitably powered trial with overall survival as the primary endpoint was not judged feasible. Although mature survival data (as a secondary endpoint) are not yet available, the large improvement in disease-free survival we noted for the primary endpoint, together with improved metastasis-free survival recorded as a secondary endpoint, strongly suggest that patients have better outcomes with chemotherapy than without.”

The incidence of acute grade 3 or worse treatment-emergent adverse events was 44% in the chemotherapy arm and 4% in the surveillance arm (P less than .0001). Quality of life was worse for the chemotherapy arm at 3 months (P = .0028), but that was no longer the case at 12 months (P = .20). There were no treatment-related deaths.

“[A]djuvant platinum-based chemotherapy should be adopted as a new standard of care for patients with locally advanced UTUC for whom systemic chemotherapy is not contraindicated,” the investigators recommended. “This regimen should be routinely considered for all patients in this population, and future studies should focus on combinations with novel agents in the adjuvant setting, which might further improve the prognosis for locally advanced UTUC.”

The trial was funded by Cancer Research UK. The authors disclosed relationships with numerous pharmaceutical companies.

SOURCE: Birtle A et al. Lancet. 2020 Mar 5. doi: 10.1016/S0140-6736(20)30415-3.

SAN FRANCISCO – A large share of men with testicular cancer undergoing postchemotherapy retroperitoneal lymph node dissection (RPLND) may be having organs unnecessarily removed at the time, a retrospective analysis suggests.

However, determining which of these patients do not require adjunct resection remains challenging, according to Tim Nestler, MD, of the University Hospital of Cologne in Germany.

Dr. Nestler presented the retrospective analysis at the the 2020 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Nestler and his colleagues analyzed the frequency and pathologic findings of adjunctive organ resection (encompassing organs, blood vessels, and bones) among 1,181 men undergoing postchemotherapy RPLND during 2008-2018.

Adjunctive organ resection was performed in 20% of patients. Pathologic evaluation of the resection specimens showed viable germ cell tumors in 21.7% of these patients, teratomas in 38.7%, and necrosis or fibrosis in 39.6%. The prevalence of necrosis/fibrosis was generally similar across various organs, blood vessels, and bones.

At a median follow-up of 22 months, 27% of the study cohort experienced a relapse. The 5-year rate of relapse-free survival was 18% for patients with viable germ cell tumors in adjunctively resected organs, 54% for those with teratomas, and 81% for those with necrosis/fibrosis.

“Within this cohort, about 40% of all resections finally showed necrosis/fibrosis, and these are patients that were kind of unnecessarily treated from the oncological standpoint,” Dr. Nestler said, although he noted that such resections should continue until there is a reliable way to identify this subset of patients.

“We are thinking of increasing the rate of frozen sections within surgery, especially to avoid nephrectomies, hepatectomies, and vascular resections,” he said. “Or, if we are thinking about bone metastasis, then we also might think about presurgical biopsies.”

Stepping back even further, clinicians could do “a more accurate presurgical work-up to identify those patients that are really in need of postchemotherapy RPLND, compared to those who will have a high chance of showing necrosis/fibrosis,” Dr. Nestler said. “Here, we are currently working on means like radiomics and molecular markers.”
 

Implications for patient counseling

“The problem is, and this is the central crux of the issue, that we cannot accurately identify ‘cancer or teratoma’ from ‘not cancer or teratoma’ prior to surgery,” said session cochair Brant A. Inman, MD, of the Duke Prostate and Urologic Cancer Center in Durham, N.C.

Preoperative biopsies are not helpful in differentiating these groups because of their technical difficulty and very high false-negative rate, Dr. Inman said. And intraoperative biopsies with frozen sections have the same sampling problem, plus problems of diagnostic accuracy and differentiation of live from dead tumor.

“This research is mainly helpful for preoperative patient counseling,” Dr. Inman said. “You have to tell your patient prior to RPLND, especially if they have a large postchemotherapy mass, several things.”

Specifically, patients should be informed about the probability of needing adjunctive resection and what that entails, he said. If this additional surgery is needed, patients should be informed of the probability that the tissues removed will not contain any cancer or teratoma. Moreover, “if this is the case, the blood vessel or organ will likely have been removed without benefit to you,” he added.

Finally, patients should be told that “there is no accurate way presently to distinguish cancer/teratoma from necrosis/fibrosis preoperatively or intraoperatively, including imaging and biopsies,” Dr. Inman said. “New technologies, like microRNA tests, are being developed to help sort this out.”

There was no funding for this research. Dr. Nestler disclosed no relevant conflicts of interest. Dr. Inman disclosed relationships with several pharmaceutical companies as well as patents or royalties for soluble B7-H1.

SOURCE: Nestler T et al. GUCS 2020, Abstract 388.

SAN FRANCISCO – A large share of men with testicular cancer undergoing postchemotherapy retroperitoneal lymph node dissection (RPLND) may be having organs unnecessarily removed at the time, a retrospective analysis suggests.

However, determining which of these patients do not require adjunct resection remains challenging, according to Tim Nestler, MD, of the University Hospital of Cologne in Germany.

Dr. Nestler presented the retrospective analysis at the the 2020 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Nestler and his colleagues analyzed the frequency and pathologic findings of adjunctive organ resection (encompassing organs, blood vessels, and bones) among 1,181 men undergoing postchemotherapy RPLND during 2008-2018.

Adjunctive organ resection was performed in 20% of patients. Pathologic evaluation of the resection specimens showed viable germ cell tumors in 21.7% of these patients, teratomas in 38.7%, and necrosis or fibrosis in 39.6%. The prevalence of necrosis/fibrosis was generally similar across various organs, blood vessels, and bones.

At a median follow-up of 22 months, 27% of the study cohort experienced a relapse. The 5-year rate of relapse-free survival was 18% for patients with viable germ cell tumors in adjunctively resected organs, 54% for those with teratomas, and 81% for those with necrosis/fibrosis.

“Within this cohort, about 40% of all resections finally showed necrosis/fibrosis, and these are patients that were kind of unnecessarily treated from the oncological standpoint,” Dr. Nestler said, although he noted that such resections should continue until there is a reliable way to identify this subset of patients.

“We are thinking of increasing the rate of frozen sections within surgery, especially to avoid nephrectomies, hepatectomies, and vascular resections,” he said. “Or, if we are thinking about bone metastasis, then we also might think about presurgical biopsies.”

Stepping back even further, clinicians could do “a more accurate presurgical work-up to identify those patients that are really in need of postchemotherapy RPLND, compared to those who will have a high chance of showing necrosis/fibrosis,” Dr. Nestler said. “Here, we are currently working on means like radiomics and molecular markers.”
 

Implications for patient counseling

“The problem is, and this is the central crux of the issue, that we cannot accurately identify ‘cancer or teratoma’ from ‘not cancer or teratoma’ prior to surgery,” said session cochair Brant A. Inman, MD, of the Duke Prostate and Urologic Cancer Center in Durham, N.C.

Preoperative biopsies are not helpful in differentiating these groups because of their technical difficulty and very high false-negative rate, Dr. Inman said. And intraoperative biopsies with frozen sections have the same sampling problem, plus problems of diagnostic accuracy and differentiation of live from dead tumor.

“This research is mainly helpful for preoperative patient counseling,” Dr. Inman said. “You have to tell your patient prior to RPLND, especially if they have a large postchemotherapy mass, several things.”

Specifically, patients should be informed about the probability of needing adjunctive resection and what that entails, he said. If this additional surgery is needed, patients should be informed of the probability that the tissues removed will not contain any cancer or teratoma. Moreover, “if this is the case, the blood vessel or organ will likely have been removed without benefit to you,” he added.

Finally, patients should be told that “there is no accurate way presently to distinguish cancer/teratoma from necrosis/fibrosis preoperatively or intraoperatively, including imaging and biopsies,” Dr. Inman said. “New technologies, like microRNA tests, are being developed to help sort this out.”

There was no funding for this research. Dr. Nestler disclosed no relevant conflicts of interest. Dr. Inman disclosed relationships with several pharmaceutical companies as well as patents or royalties for soluble B7-H1.

SOURCE: Nestler T et al. GUCS 2020, Abstract 388.

SAN FRANCISCO – A large share of men with testicular cancer undergoing postchemotherapy retroperitoneal lymph node dissection (RPLND) may be having organs unnecessarily removed at the time, a retrospective analysis suggests.

However, determining which of these patients do not require adjunct resection remains challenging, according to Tim Nestler, MD, of the University Hospital of Cologne in Germany.

Dr. Nestler presented the retrospective analysis at the the 2020 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Nestler and his colleagues analyzed the frequency and pathologic findings of adjunctive organ resection (encompassing organs, blood vessels, and bones) among 1,181 men undergoing postchemotherapy RPLND during 2008-2018.

Adjunctive organ resection was performed in 20% of patients. Pathologic evaluation of the resection specimens showed viable germ cell tumors in 21.7% of these patients, teratomas in 38.7%, and necrosis or fibrosis in 39.6%. The prevalence of necrosis/fibrosis was generally similar across various organs, blood vessels, and bones.

At a median follow-up of 22 months, 27% of the study cohort experienced a relapse. The 5-year rate of relapse-free survival was 18% for patients with viable germ cell tumors in adjunctively resected organs, 54% for those with teratomas, and 81% for those with necrosis/fibrosis.

“Within this cohort, about 40% of all resections finally showed necrosis/fibrosis, and these are patients that were kind of unnecessarily treated from the oncological standpoint,” Dr. Nestler said, although he noted that such resections should continue until there is a reliable way to identify this subset of patients.

“We are thinking of increasing the rate of frozen sections within surgery, especially to avoid nephrectomies, hepatectomies, and vascular resections,” he said. “Or, if we are thinking about bone metastasis, then we also might think about presurgical biopsies.”

Stepping back even further, clinicians could do “a more accurate presurgical work-up to identify those patients that are really in need of postchemotherapy RPLND, compared to those who will have a high chance of showing necrosis/fibrosis,” Dr. Nestler said. “Here, we are currently working on means like radiomics and molecular markers.”
 

Implications for patient counseling

“The problem is, and this is the central crux of the issue, that we cannot accurately identify ‘cancer or teratoma’ from ‘not cancer or teratoma’ prior to surgery,” said session cochair Brant A. Inman, MD, of the Duke Prostate and Urologic Cancer Center in Durham, N.C.

Preoperative biopsies are not helpful in differentiating these groups because of their technical difficulty and very high false-negative rate, Dr. Inman said. And intraoperative biopsies with frozen sections have the same sampling problem, plus problems of diagnostic accuracy and differentiation of live from dead tumor.

“This research is mainly helpful for preoperative patient counseling,” Dr. Inman said. “You have to tell your patient prior to RPLND, especially if they have a large postchemotherapy mass, several things.”

Specifically, patients should be informed about the probability of needing adjunctive resection and what that entails, he said. If this additional surgery is needed, patients should be informed of the probability that the tissues removed will not contain any cancer or teratoma. Moreover, “if this is the case, the blood vessel or organ will likely have been removed without benefit to you,” he added.

Finally, patients should be told that “there is no accurate way presently to distinguish cancer/teratoma from necrosis/fibrosis preoperatively or intraoperatively, including imaging and biopsies,” Dr. Inman said. “New technologies, like microRNA tests, are being developed to help sort this out.”

There was no funding for this research. Dr. Nestler disclosed no relevant conflicts of interest. Dr. Inman disclosed relationships with several pharmaceutical companies as well as patents or royalties for soluble B7-H1.

SOURCE: Nestler T et al. GUCS 2020, Abstract 388.

SAN FRANCISCO – A novel gene therapy may expand treatment options for non–muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin (BCG), new research suggests.

Susan London/MDedge News

The therapy, nadofaragene firadenovec, is a recombinant adenovirus that is instilled into the bladder and delivers the human interferon alpha-2b gene, leading to expression of the immune cytokine.

At 3 months, nadofaragene firadenovec had produced a complete response in 53.4% of patients with carcinoma in situ (CIS), and the rate of high-grade recurrence-free survival was 59.6% in all patients. Although most patients (70.1%) experienced adverse events in this trial, few had serious events (1.9%).

Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minn., presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“The optimal management for patients with BCG-unresponsive non–muscle invasive bladder cancer remains to be established,” Dr. Boorjian said. “National and organizational guidelines recommend radical cystectomy in this setting, but we have to acknowledge that many of our patients will be either unwilling or unfit to undergo what is often a highly morbid operation.”

Dr. Boorjian and coinvestigators tested nadofaragene firadenovec in 107 patients with CIS, with or without high-grade Ta or T1 papillary disease, as well as 50 patients with high-grade Ta or T1 papillary disease only.

All patients received nadofaragene firadenovec once every 3 months for up four doses, with additional dosing at the investigator’s discretion. Although the trial was designated as phase 3, it did not have the typical randomized comparative design.

“The challenge in the BCG-unresponsive disease state is that, historically, there has been no validated good comparator to use here; there’s no standard of care for these patients,” Dr. Boorjian explained, noting that the design was chosen after discussion with the Food and Drug Administration.
 

Efficacy

The complete response rate among CIS patients at any time after instillation, the trial’s primary objective, was 53.4%. All of these responses occurred after a single dose of nadofaragene firadenovec. Responses were considered durable, as 45.5% of CIS patients who had a complete response at 3 months still had a complete response at 12 months.

The rate of high-grade recurrence-free survival at 3 months was 59.6% in the overall population, 53.4% in patients with CIS, and 72.9% in patients with papillary disease. At 12 months, the rate of high-grade recurrence-free survival was 30.5%, 24.3%, and 43.8%, respectively.

The rate of high-grade recurrence without muscle invasive bladder cancer was 71.8% in the CIS group and 52.1% in the papillary group. The rate of progression to muscle invasive bladder cancer or more advanced disease was 4.9% and 6.3%, respectively. The overall 2-year rate of cystectomy-free survival was 64%, and there were no bladder cancer deaths.
 

Safety

Nadofaragene firadenovec was considered safe and well tolerated. The most common study drug–related adverse events were irritative voiding symptoms, such as discharge, bladder spasm, micturition urgency, and hematuria.

Although 70.1% of patients experienced a local or systemic adverse event related to the study drug or procedure, few experienced serious adverse events (1.9%), grade 3 adverse events (3.8%), or treatment-emergent adverse events leading to discontinuation (1.9%). The serious adverse events were sepsis, syncope, and hematuria.
 

Next steps

“Nadofaragene firadenovec represents a promising option for patients with BCG-unresponsive [non–muscle invasive bladder cancer],” Dr. Boorjian said. “What we want to see going forward is durability of response, cystectomy-free survival, and metastasis-free and cancer-specific survival. Those are the harder endpoints that, as these data mature, we will want to see so that we are able to counsel our patients accordingly.”

Susan London/MDedge News

The FDA recently approved pembrolizumab for this patient population, noted session cochair Guru Sonpavde, MD, of the Dana-Farber Cancer Institute in Boston.

“But nadofaragene firadenovec is much less toxic, it is given intravesically, and it’s only given once every 3 months,” he said. “The outcomes at the 1-year point look similar in terms of the durable complete response rate. So we hope that this therapy will be able to get to the clinic, but we have to wait for the FDA to decide.”

It remains to be seen how nadofaragene firadenovec compares with other emerging therapies for high-risk BCG-unresponsive non–muscle invasive bladder cancer, including pembrolizumab and potentially intravesical oportuzumab monatox (a targeted immunotoxin) and intravesical combination BCG and superagonist interleukin-15 (ALT-803), according to Dr. Boorjian.

“A unique feature of the trial I presented was that the results were validated by a mandatory 12-month study biopsy, which has not been the case in other trials,” he pointed out. “So this separates it a little bit when you are looking at pathologic response rates and high-grade recurrence–free rates. They are based on pathologic confirmation.”

Evaluators will ultimately compare these therapies on safety, efficacy, ease of administration, delivery schedule, and cost, Dr. Boorjian said. “At this stage, it’s very difficult to start to say which agent is going to be placed where in our management paradigm. We have to go step by step: Do the trial that we did, show our data, put it out for review, and then allow the community to engage in a discussion about which agent, and why, for which patient.”

This trial was funded by FKD Therapies Oy. Dr. Boorjian disclosed relationships with Ferring and Sanofi. Dr. Sonpavde disclosed relationships with many companies.

SOURCE: Boorjian SA et al. GUCS 2020, Abstract 442.

SAN FRANCISCO – A novel gene therapy may expand treatment options for non–muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin (BCG), new research suggests.

Susan London/MDedge News

The therapy, nadofaragene firadenovec, is a recombinant adenovirus that is instilled into the bladder and delivers the human interferon alpha-2b gene, leading to expression of the immune cytokine.

At 3 months, nadofaragene firadenovec had produced a complete response in 53.4% of patients with carcinoma in situ (CIS), and the rate of high-grade recurrence-free survival was 59.6% in all patients. Although most patients (70.1%) experienced adverse events in this trial, few had serious events (1.9%).

Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minn., presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“The optimal management for patients with BCG-unresponsive non–muscle invasive bladder cancer remains to be established,” Dr. Boorjian said. “National and organizational guidelines recommend radical cystectomy in this setting, but we have to acknowledge that many of our patients will be either unwilling or unfit to undergo what is often a highly morbid operation.”

Dr. Boorjian and coinvestigators tested nadofaragene firadenovec in 107 patients with CIS, with or without high-grade Ta or T1 papillary disease, as well as 50 patients with high-grade Ta or T1 papillary disease only.

All patients received nadofaragene firadenovec once every 3 months for up four doses, with additional dosing at the investigator’s discretion. Although the trial was designated as phase 3, it did not have the typical randomized comparative design.

“The challenge in the BCG-unresponsive disease state is that, historically, there has been no validated good comparator to use here; there’s no standard of care for these patients,” Dr. Boorjian explained, noting that the design was chosen after discussion with the Food and Drug Administration.
 

Efficacy

The complete response rate among CIS patients at any time after instillation, the trial’s primary objective, was 53.4%. All of these responses occurred after a single dose of nadofaragene firadenovec. Responses were considered durable, as 45.5% of CIS patients who had a complete response at 3 months still had a complete response at 12 months.

The rate of high-grade recurrence-free survival at 3 months was 59.6% in the overall population, 53.4% in patients with CIS, and 72.9% in patients with papillary disease. At 12 months, the rate of high-grade recurrence-free survival was 30.5%, 24.3%, and 43.8%, respectively.

The rate of high-grade recurrence without muscle invasive bladder cancer was 71.8% in the CIS group and 52.1% in the papillary group. The rate of progression to muscle invasive bladder cancer or more advanced disease was 4.9% and 6.3%, respectively. The overall 2-year rate of cystectomy-free survival was 64%, and there were no bladder cancer deaths.
 

Safety

Nadofaragene firadenovec was considered safe and well tolerated. The most common study drug–related adverse events were irritative voiding symptoms, such as discharge, bladder spasm, micturition urgency, and hematuria.

Although 70.1% of patients experienced a local or systemic adverse event related to the study drug or procedure, few experienced serious adverse events (1.9%), grade 3 adverse events (3.8%), or treatment-emergent adverse events leading to discontinuation (1.9%). The serious adverse events were sepsis, syncope, and hematuria.
 

Next steps

“Nadofaragene firadenovec represents a promising option for patients with BCG-unresponsive [non–muscle invasive bladder cancer],” Dr. Boorjian said. “What we want to see going forward is durability of response, cystectomy-free survival, and metastasis-free and cancer-specific survival. Those are the harder endpoints that, as these data mature, we will want to see so that we are able to counsel our patients accordingly.”

Susan London/MDedge News

The FDA recently approved pembrolizumab for this patient population, noted session cochair Guru Sonpavde, MD, of the Dana-Farber Cancer Institute in Boston.

“But nadofaragene firadenovec is much less toxic, it is given intravesically, and it’s only given once every 3 months,” he said. “The outcomes at the 1-year point look similar in terms of the durable complete response rate. So we hope that this therapy will be able to get to the clinic, but we have to wait for the FDA to decide.”

It remains to be seen how nadofaragene firadenovec compares with other emerging therapies for high-risk BCG-unresponsive non–muscle invasive bladder cancer, including pembrolizumab and potentially intravesical oportuzumab monatox (a targeted immunotoxin) and intravesical combination BCG and superagonist interleukin-15 (ALT-803), according to Dr. Boorjian.

“A unique feature of the trial I presented was that the results were validated by a mandatory 12-month study biopsy, which has not been the case in other trials,” he pointed out. “So this separates it a little bit when you are looking at pathologic response rates and high-grade recurrence–free rates. They are based on pathologic confirmation.”

Evaluators will ultimately compare these therapies on safety, efficacy, ease of administration, delivery schedule, and cost, Dr. Boorjian said. “At this stage, it’s very difficult to start to say which agent is going to be placed where in our management paradigm. We have to go step by step: Do the trial that we did, show our data, put it out for review, and then allow the community to engage in a discussion about which agent, and why, for which patient.”

This trial was funded by FKD Therapies Oy. Dr. Boorjian disclosed relationships with Ferring and Sanofi. Dr. Sonpavde disclosed relationships with many companies.

SOURCE: Boorjian SA et al. GUCS 2020, Abstract 442.

SAN FRANCISCO – A novel gene therapy may expand treatment options for non–muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin (BCG), new research suggests.

Susan London/MDedge News

The therapy, nadofaragene firadenovec, is a recombinant adenovirus that is instilled into the bladder and delivers the human interferon alpha-2b gene, leading to expression of the immune cytokine.

At 3 months, nadofaragene firadenovec had produced a complete response in 53.4% of patients with carcinoma in situ (CIS), and the rate of high-grade recurrence-free survival was 59.6% in all patients. Although most patients (70.1%) experienced adverse events in this trial, few had serious events (1.9%).

Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minn., presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“The optimal management for patients with BCG-unresponsive non–muscle invasive bladder cancer remains to be established,” Dr. Boorjian said. “National and organizational guidelines recommend radical cystectomy in this setting, but we have to acknowledge that many of our patients will be either unwilling or unfit to undergo what is often a highly morbid operation.”

Dr. Boorjian and coinvestigators tested nadofaragene firadenovec in 107 patients with CIS, with or without high-grade Ta or T1 papillary disease, as well as 50 patients with high-grade Ta or T1 papillary disease only.

All patients received nadofaragene firadenovec once every 3 months for up four doses, with additional dosing at the investigator’s discretion. Although the trial was designated as phase 3, it did not have the typical randomized comparative design.

“The challenge in the BCG-unresponsive disease state is that, historically, there has been no validated good comparator to use here; there’s no standard of care for these patients,” Dr. Boorjian explained, noting that the design was chosen after discussion with the Food and Drug Administration.
 

Efficacy

The complete response rate among CIS patients at any time after instillation, the trial’s primary objective, was 53.4%. All of these responses occurred after a single dose of nadofaragene firadenovec. Responses were considered durable, as 45.5% of CIS patients who had a complete response at 3 months still had a complete response at 12 months.

The rate of high-grade recurrence-free survival at 3 months was 59.6% in the overall population, 53.4% in patients with CIS, and 72.9% in patients with papillary disease. At 12 months, the rate of high-grade recurrence-free survival was 30.5%, 24.3%, and 43.8%, respectively.

The rate of high-grade recurrence without muscle invasive bladder cancer was 71.8% in the CIS group and 52.1% in the papillary group. The rate of progression to muscle invasive bladder cancer or more advanced disease was 4.9% and 6.3%, respectively. The overall 2-year rate of cystectomy-free survival was 64%, and there were no bladder cancer deaths.
 

Safety

Nadofaragene firadenovec was considered safe and well tolerated. The most common study drug–related adverse events were irritative voiding symptoms, such as discharge, bladder spasm, micturition urgency, and hematuria.

Although 70.1% of patients experienced a local or systemic adverse event related to the study drug or procedure, few experienced serious adverse events (1.9%), grade 3 adverse events (3.8%), or treatment-emergent adverse events leading to discontinuation (1.9%). The serious adverse events were sepsis, syncope, and hematuria.
 

Next steps

“Nadofaragene firadenovec represents a promising option for patients with BCG-unresponsive [non–muscle invasive bladder cancer],” Dr. Boorjian said. “What we want to see going forward is durability of response, cystectomy-free survival, and metastasis-free and cancer-specific survival. Those are the harder endpoints that, as these data mature, we will want to see so that we are able to counsel our patients accordingly.”

Susan London/MDedge News

The FDA recently approved pembrolizumab for this patient population, noted session cochair Guru Sonpavde, MD, of the Dana-Farber Cancer Institute in Boston.

“But nadofaragene firadenovec is much less toxic, it is given intravesically, and it’s only given once every 3 months,” he said. “The outcomes at the 1-year point look similar in terms of the durable complete response rate. So we hope that this therapy will be able to get to the clinic, but we have to wait for the FDA to decide.”

It remains to be seen how nadofaragene firadenovec compares with other emerging therapies for high-risk BCG-unresponsive non–muscle invasive bladder cancer, including pembrolizumab and potentially intravesical oportuzumab monatox (a targeted immunotoxin) and intravesical combination BCG and superagonist interleukin-15 (ALT-803), according to Dr. Boorjian.

“A unique feature of the trial I presented was that the results were validated by a mandatory 12-month study biopsy, which has not been the case in other trials,” he pointed out. “So this separates it a little bit when you are looking at pathologic response rates and high-grade recurrence–free rates. They are based on pathologic confirmation.”

Evaluators will ultimately compare these therapies on safety, efficacy, ease of administration, delivery schedule, and cost, Dr. Boorjian said. “At this stage, it’s very difficult to start to say which agent is going to be placed where in our management paradigm. We have to go step by step: Do the trial that we did, show our data, put it out for review, and then allow the community to engage in a discussion about which agent, and why, for which patient.”

This trial was funded by FKD Therapies Oy. Dr. Boorjian disclosed relationships with Ferring and Sanofi. Dr. Sonpavde disclosed relationships with many companies.

SOURCE: Boorjian SA et al. GUCS 2020, Abstract 442.