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Active psoriatic arthritis, ankylosing spondylitis linked to increase in adverse pregnancy outcomes
Women with psoriatic arthritis and ankylosing spondylitis generally have favorable pregnancy outcomes, but high disease activity during pregnancy could increase the risk of adverse labor and delivery outcomes, according to 2004-2018 data from the Organization of Teratology Information Specialists (OTIS) Autoimmune Disease Project.
Corticosteroid use further increased risk for preterm delivery among women with ankylosing spondylitis.
While more research is needed, these findings suggest that better obstetric outcomes might be achieved via better disease control and minimal use of corticosteroids, according to Chelsey J. F. Smith, MD, of the University of California, San Diego, and colleagues.
“Future studies are needed to confirm the novel findings seen in our study, as well as to continue to analyze the effect of different disease activity measures and medication use on pregnancy outcomes in these two chronic conditions,” Dr. Smith and coauthors said in a report on the study in Arthritis Care and Research.
Many women affected by psoriatic arthritis and ankylosing spondylitis are of child-bearing age and consider planning a family, according to the researchers. Data on pregnancy outcomes are lacking, they said, “often making it difficult for rheumatologists and obstetricians to counsel their patients effectively.”
The study from Dr. Smith and coinvestigators comprised 963 women who enrolled in the OTIS prospective cohort study within 20 weeks of gestation and delivered at least one live-born infant. Of that cohort, 129 had ankylosing spondylitis, 117 had psoriatic arthritis, and the remaining 717 served as a control group.
Psoriatic arthritis conferred an 81% increased risk for moderate preterm delivery at 32-36 weeks gestation, compared with healthier women, 13.7% and 7.7% respectively. Risk was increased among women with psoriatic arthritis for preterm labor, 16.2% and 8.4% (adjusted risk ratio, 2.05, 95% confidence interval, 1.21-3.48), caesarean delivery, 48.7% and 26.2% (aRR, 1.63, 95% CI, 1.26-2.12), and oligohydramnios, 25% and 11% (aRR, 3.79, 95% CI, 1.34-10.74). Women with psoriatic arthritis were 2 years older on average and their average body mass index was 27 kg/m2 vs. 24.5 kg/m2 in the control group.
In women with ankylosing spondylitis, risk of infant hospitalization in the neonatal intensive care unit was increased by 67%, 17.2% vs. 11.9% in the control group.
Active disease measured by the Health Assessment Questionnaire (HAQ) or Routine Assessment of Patient Index Data 3 (RAPID3) was linked to increased risk of adverse obstetric outcomes in some cases, the investigators said.
For example, risk of preterm delivery was increased in women with psoriatic arthritis who had active disease at 32 weeks as measured by HAQ (27 women) and RAPID3 (28 women) scores, while in ankylosing spondylitis, active disease measured at intake by RAPID3 (46 women) was associated with increased risk of caesarean delivery.
Medication use in women with psoriatic arthritis was not associated with increased preterm delivery risk. However, women with ankylosing spondylitis who used corticosteroids in the second trimester had an increased risk of preterm delivery.
The rate of corticosteroid use was “surprisingly high” at 38% among the women with ankylosing spondylitis, Dr. Smith and coinvestigators said.
“The 2016 American College of Rheumatology guidelines in fact recommend against the use of systemic corticosteroids for the treatment of ankylosing spondylitis, with the exception of short-term treatment with rapid tapering in circumstances such as flares during pregnancy, flares of concomitant inflammatory bowel disease, or flare of peripheral arthritis,” they said in their report.
Dr. Smith and coauthors reported no conflicts of interest. The OTIS Collaborative Research Group has received research funding from AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Pfizer, and others.
SOURCE: Smith CJF et al. Arthritis Care Res. 2019 May 10. doi: 10.1002/acr.23924.
Women with psoriatic arthritis and ankylosing spondylitis generally have favorable pregnancy outcomes, but high disease activity during pregnancy could increase the risk of adverse labor and delivery outcomes, according to 2004-2018 data from the Organization of Teratology Information Specialists (OTIS) Autoimmune Disease Project.
Corticosteroid use further increased risk for preterm delivery among women with ankylosing spondylitis.
While more research is needed, these findings suggest that better obstetric outcomes might be achieved via better disease control and minimal use of corticosteroids, according to Chelsey J. F. Smith, MD, of the University of California, San Diego, and colleagues.
“Future studies are needed to confirm the novel findings seen in our study, as well as to continue to analyze the effect of different disease activity measures and medication use on pregnancy outcomes in these two chronic conditions,” Dr. Smith and coauthors said in a report on the study in Arthritis Care and Research.
Many women affected by psoriatic arthritis and ankylosing spondylitis are of child-bearing age and consider planning a family, according to the researchers. Data on pregnancy outcomes are lacking, they said, “often making it difficult for rheumatologists and obstetricians to counsel their patients effectively.”
The study from Dr. Smith and coinvestigators comprised 963 women who enrolled in the OTIS prospective cohort study within 20 weeks of gestation and delivered at least one live-born infant. Of that cohort, 129 had ankylosing spondylitis, 117 had psoriatic arthritis, and the remaining 717 served as a control group.
Psoriatic arthritis conferred an 81% increased risk for moderate preterm delivery at 32-36 weeks gestation, compared with healthier women, 13.7% and 7.7% respectively. Risk was increased among women with psoriatic arthritis for preterm labor, 16.2% and 8.4% (adjusted risk ratio, 2.05, 95% confidence interval, 1.21-3.48), caesarean delivery, 48.7% and 26.2% (aRR, 1.63, 95% CI, 1.26-2.12), and oligohydramnios, 25% and 11% (aRR, 3.79, 95% CI, 1.34-10.74). Women with psoriatic arthritis were 2 years older on average and their average body mass index was 27 kg/m2 vs. 24.5 kg/m2 in the control group.
In women with ankylosing spondylitis, risk of infant hospitalization in the neonatal intensive care unit was increased by 67%, 17.2% vs. 11.9% in the control group.
Active disease measured by the Health Assessment Questionnaire (HAQ) or Routine Assessment of Patient Index Data 3 (RAPID3) was linked to increased risk of adverse obstetric outcomes in some cases, the investigators said.
For example, risk of preterm delivery was increased in women with psoriatic arthritis who had active disease at 32 weeks as measured by HAQ (27 women) and RAPID3 (28 women) scores, while in ankylosing spondylitis, active disease measured at intake by RAPID3 (46 women) was associated with increased risk of caesarean delivery.
Medication use in women with psoriatic arthritis was not associated with increased preterm delivery risk. However, women with ankylosing spondylitis who used corticosteroids in the second trimester had an increased risk of preterm delivery.
The rate of corticosteroid use was “surprisingly high” at 38% among the women with ankylosing spondylitis, Dr. Smith and coinvestigators said.
“The 2016 American College of Rheumatology guidelines in fact recommend against the use of systemic corticosteroids for the treatment of ankylosing spondylitis, with the exception of short-term treatment with rapid tapering in circumstances such as flares during pregnancy, flares of concomitant inflammatory bowel disease, or flare of peripheral arthritis,” they said in their report.
Dr. Smith and coauthors reported no conflicts of interest. The OTIS Collaborative Research Group has received research funding from AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Pfizer, and others.
SOURCE: Smith CJF et al. Arthritis Care Res. 2019 May 10. doi: 10.1002/acr.23924.
Women with psoriatic arthritis and ankylosing spondylitis generally have favorable pregnancy outcomes, but high disease activity during pregnancy could increase the risk of adverse labor and delivery outcomes, according to 2004-2018 data from the Organization of Teratology Information Specialists (OTIS) Autoimmune Disease Project.
Corticosteroid use further increased risk for preterm delivery among women with ankylosing spondylitis.
While more research is needed, these findings suggest that better obstetric outcomes might be achieved via better disease control and minimal use of corticosteroids, according to Chelsey J. F. Smith, MD, of the University of California, San Diego, and colleagues.
“Future studies are needed to confirm the novel findings seen in our study, as well as to continue to analyze the effect of different disease activity measures and medication use on pregnancy outcomes in these two chronic conditions,” Dr. Smith and coauthors said in a report on the study in Arthritis Care and Research.
Many women affected by psoriatic arthritis and ankylosing spondylitis are of child-bearing age and consider planning a family, according to the researchers. Data on pregnancy outcomes are lacking, they said, “often making it difficult for rheumatologists and obstetricians to counsel their patients effectively.”
The study from Dr. Smith and coinvestigators comprised 963 women who enrolled in the OTIS prospective cohort study within 20 weeks of gestation and delivered at least one live-born infant. Of that cohort, 129 had ankylosing spondylitis, 117 had psoriatic arthritis, and the remaining 717 served as a control group.
Psoriatic arthritis conferred an 81% increased risk for moderate preterm delivery at 32-36 weeks gestation, compared with healthier women, 13.7% and 7.7% respectively. Risk was increased among women with psoriatic arthritis for preterm labor, 16.2% and 8.4% (adjusted risk ratio, 2.05, 95% confidence interval, 1.21-3.48), caesarean delivery, 48.7% and 26.2% (aRR, 1.63, 95% CI, 1.26-2.12), and oligohydramnios, 25% and 11% (aRR, 3.79, 95% CI, 1.34-10.74). Women with psoriatic arthritis were 2 years older on average and their average body mass index was 27 kg/m2 vs. 24.5 kg/m2 in the control group.
In women with ankylosing spondylitis, risk of infant hospitalization in the neonatal intensive care unit was increased by 67%, 17.2% vs. 11.9% in the control group.
Active disease measured by the Health Assessment Questionnaire (HAQ) or Routine Assessment of Patient Index Data 3 (RAPID3) was linked to increased risk of adverse obstetric outcomes in some cases, the investigators said.
For example, risk of preterm delivery was increased in women with psoriatic arthritis who had active disease at 32 weeks as measured by HAQ (27 women) and RAPID3 (28 women) scores, while in ankylosing spondylitis, active disease measured at intake by RAPID3 (46 women) was associated with increased risk of caesarean delivery.
Medication use in women with psoriatic arthritis was not associated with increased preterm delivery risk. However, women with ankylosing spondylitis who used corticosteroids in the second trimester had an increased risk of preterm delivery.
The rate of corticosteroid use was “surprisingly high” at 38% among the women with ankylosing spondylitis, Dr. Smith and coinvestigators said.
“The 2016 American College of Rheumatology guidelines in fact recommend against the use of systemic corticosteroids for the treatment of ankylosing spondylitis, with the exception of short-term treatment with rapid tapering in circumstances such as flares during pregnancy, flares of concomitant inflammatory bowel disease, or flare of peripheral arthritis,” they said in their report.
Dr. Smith and coauthors reported no conflicts of interest. The OTIS Collaborative Research Group has received research funding from AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Pfizer, and others.
SOURCE: Smith CJF et al. Arthritis Care Res. 2019 May 10. doi: 10.1002/acr.23924.
FROM ARTHRITIS CARE & RESEARCH
Antiangiogenics linked to fatal bleeds after RT in patients with “ultracentral” lung tumors
In patients with tumors bordering the central airway, use of antiangiogenic agents has been linked to fatal hemorrhage after radiation treatment, according to investigators reporting a large, retrospective case series.
Most hemorrhagic events in these patients with so-called “ultracentral” lung tumors occurred in those who received bevacizumab or pazopanib within 30 days of stereotactic body radiation therapy (SBRT), according to radiation oncologist Abraham J. Wu, MD, and coinvestigators at Memorial Sloan Kettering Cancer Center in New York.
Based on these new data, the combination of antiangiogenic agents (AAAs) and SBRT should be avoided in patients with ultracentral lung tumors, the researchers wrote.
“Although this report is limited by its retrospective nature, these findings strongly suggest that AAAs potentiate severe SBRT-related toxic effects,” Dr. Wu and coinvestigators wrote in a report on the study in JAMA Oncology. While AAAs are not indicated for treatment of patients with early-stage lung cancer, they may be used to treat oligometastatic disease, which may also be treated with SBRT.
The study included 88 patients with a median age of 74 years who had a lung tumor abutting the proximal bronchial tree, a planned target volume overlapping the esophagus, or both. There were lung metastases in 35 patients.
Nine patients had received bevacizumab, pazopanib, or ramucirumab, stopping a median of 30 days prior to SBRT and resuming a median of 29 days after the end of the radiation treatment.
There were six fatal pulmonary hemorrhages in 19.6 months of follow-up, Dr. Wu and coinvestigators reported. Of those six patients, four had received an antiangiogenic agent (three bevacizumab, one pazopanib) within 30 days of SBRT.
The probability of fatal pulmonary hemorrhage was significantly higher in the patients receiving AAAs versus those who did not (hazard ratio, 16.9; 95% confidence interval, 3.2-88.8; P less than .001).
Another six patients received AAAs more than 90 days before or after SBRT, and none of them had fatal hemorrhages.
A high rate of fatal hemorrhage was reported in another recent study of patients with ultracentral lung tumors, but that study did not identify any risk factors related to this toxic effect, Dr. Wu and coauthors wrote.
The research was partly supported by the National Institutes of Health, the China Scholarship Council, and the Joanne & John Dallepezze Foundation. The investigators reported disclosures related to AstraZeneca, CivaTech Oncology, Alpha Tau Medical, Varian Medical Systems, Boehringer Ingelheim, Pfizer, Merck, and Elekta.
SOURCE: Wu AJ et al. JAMA Oncol. 2019 Apr 4. doi: 10.1001/jamaoncol.2019.0205.
In patients with tumors bordering the central airway, use of antiangiogenic agents has been linked to fatal hemorrhage after radiation treatment, according to investigators reporting a large, retrospective case series.
Most hemorrhagic events in these patients with so-called “ultracentral” lung tumors occurred in those who received bevacizumab or pazopanib within 30 days of stereotactic body radiation therapy (SBRT), according to radiation oncologist Abraham J. Wu, MD, and coinvestigators at Memorial Sloan Kettering Cancer Center in New York.
Based on these new data, the combination of antiangiogenic agents (AAAs) and SBRT should be avoided in patients with ultracentral lung tumors, the researchers wrote.
“Although this report is limited by its retrospective nature, these findings strongly suggest that AAAs potentiate severe SBRT-related toxic effects,” Dr. Wu and coinvestigators wrote in a report on the study in JAMA Oncology. While AAAs are not indicated for treatment of patients with early-stage lung cancer, they may be used to treat oligometastatic disease, which may also be treated with SBRT.
The study included 88 patients with a median age of 74 years who had a lung tumor abutting the proximal bronchial tree, a planned target volume overlapping the esophagus, or both. There were lung metastases in 35 patients.
Nine patients had received bevacizumab, pazopanib, or ramucirumab, stopping a median of 30 days prior to SBRT and resuming a median of 29 days after the end of the radiation treatment.
There were six fatal pulmonary hemorrhages in 19.6 months of follow-up, Dr. Wu and coinvestigators reported. Of those six patients, four had received an antiangiogenic agent (three bevacizumab, one pazopanib) within 30 days of SBRT.
The probability of fatal pulmonary hemorrhage was significantly higher in the patients receiving AAAs versus those who did not (hazard ratio, 16.9; 95% confidence interval, 3.2-88.8; P less than .001).
Another six patients received AAAs more than 90 days before or after SBRT, and none of them had fatal hemorrhages.
A high rate of fatal hemorrhage was reported in another recent study of patients with ultracentral lung tumors, but that study did not identify any risk factors related to this toxic effect, Dr. Wu and coauthors wrote.
The research was partly supported by the National Institutes of Health, the China Scholarship Council, and the Joanne & John Dallepezze Foundation. The investigators reported disclosures related to AstraZeneca, CivaTech Oncology, Alpha Tau Medical, Varian Medical Systems, Boehringer Ingelheim, Pfizer, Merck, and Elekta.
SOURCE: Wu AJ et al. JAMA Oncol. 2019 Apr 4. doi: 10.1001/jamaoncol.2019.0205.
In patients with tumors bordering the central airway, use of antiangiogenic agents has been linked to fatal hemorrhage after radiation treatment, according to investigators reporting a large, retrospective case series.
Most hemorrhagic events in these patients with so-called “ultracentral” lung tumors occurred in those who received bevacizumab or pazopanib within 30 days of stereotactic body radiation therapy (SBRT), according to radiation oncologist Abraham J. Wu, MD, and coinvestigators at Memorial Sloan Kettering Cancer Center in New York.
Based on these new data, the combination of antiangiogenic agents (AAAs) and SBRT should be avoided in patients with ultracentral lung tumors, the researchers wrote.
“Although this report is limited by its retrospective nature, these findings strongly suggest that AAAs potentiate severe SBRT-related toxic effects,” Dr. Wu and coinvestigators wrote in a report on the study in JAMA Oncology. While AAAs are not indicated for treatment of patients with early-stage lung cancer, they may be used to treat oligometastatic disease, which may also be treated with SBRT.
The study included 88 patients with a median age of 74 years who had a lung tumor abutting the proximal bronchial tree, a planned target volume overlapping the esophagus, or both. There were lung metastases in 35 patients.
Nine patients had received bevacizumab, pazopanib, or ramucirumab, stopping a median of 30 days prior to SBRT and resuming a median of 29 days after the end of the radiation treatment.
There were six fatal pulmonary hemorrhages in 19.6 months of follow-up, Dr. Wu and coinvestigators reported. Of those six patients, four had received an antiangiogenic agent (three bevacizumab, one pazopanib) within 30 days of SBRT.
The probability of fatal pulmonary hemorrhage was significantly higher in the patients receiving AAAs versus those who did not (hazard ratio, 16.9; 95% confidence interval, 3.2-88.8; P less than .001).
Another six patients received AAAs more than 90 days before or after SBRT, and none of them had fatal hemorrhages.
A high rate of fatal hemorrhage was reported in another recent study of patients with ultracentral lung tumors, but that study did not identify any risk factors related to this toxic effect, Dr. Wu and coauthors wrote.
The research was partly supported by the National Institutes of Health, the China Scholarship Council, and the Joanne & John Dallepezze Foundation. The investigators reported disclosures related to AstraZeneca, CivaTech Oncology, Alpha Tau Medical, Varian Medical Systems, Boehringer Ingelheim, Pfizer, Merck, and Elekta.
SOURCE: Wu AJ et al. JAMA Oncol. 2019 Apr 4. doi: 10.1001/jamaoncol.2019.0205.
FROM JAMA ONCOLOGY
Key clinical point: In patients with tumors bordering the central airway, use of antiangiogenic agents has been linked to fatal hemorrhage after stereotactic body radiation therapy.
Major finding: There were six fatal pulmonary hemorrhages, of which four occurred in patients receiving bevacizumab or pazopanib within 30 days of stereotactic body radiation therapy.
Study details: A retrospective case series including 88 patients with lung tumors abutting the proximal bronchial tree or a planned target volume overlapping the esophagus.
Disclosures: Partial support came from the National Institutes of Health, the China Scholarship Council, and the Joanne & John Dallepezze Foundation. The investigators reported disclosures related to AstraZeneca, CivaTech Oncology, Alpha Tau Medical, Varian Medical Systems, Boehringer Ingelheim, Pfizer, Merck, and Elekta.
Source: Wu AJ et al. JAMA Oncol. 2019 Apr 4. doi: 10.1001/jamaoncol.2019.0205.
Skip metastasis rate low in node-negative oral cancers
In patients with clinically node-negative oral cavity cancers, the rate of skip metastasis to neck level IV is extremely low, according to authors of a recent meta-analysis.
The rate of level IV involvement was about 2.5%, and the rate of skip metastasis was 0.5% in the analysis, which comprised 11 retrospective studies and 2 randomized clinical trials including a total of 1,359 patients with clinically node-negative oral cavity squamous cell carcinomas.
Encountering a suspected positive lymph node during neck dissection does not appear to be an indicator of high rates of level IV involvement, according to Anton Warshavsky, MD, and colleagues in the department of otolaryngology–head and neck surgery and maxillofacial surgery at Tel Aviv Sourasky Medical Center, Israel.
“Supraomohyoid neck dissection [SOHND] is adequate for this subset of patients,” Dr. Warshavsky and coauthors wrote in a report on the study that appears in JAMA Otolaryngology–Head & Neck Surgery.
SOHND, a type of selective neck dissection, refers to removal of lymph nodes in levels I-III. This approach is now frequently used in managing clinically node-negative oral cavity squamous cell carcinoma and provides control rates similar to those associated with more extensive neck dissections, Dr. Warshavsky and colleagues wrote.
However, concern regarding the risk of skip metastases, or involvement of neck level IV without involvement of lower levels, has stirred controversy. SOHND might not be adequate in these patients because of the possibility of occult metastasis to neck level IV.
Accordingly, Dr. Warshavsky and colleagues combed the available medical literature to find relevant articles for a meta-analysis to better characterize the rate of skip metastasis to level IV in patients who had undergone neck dissection.
Level IV involvement rates in clinically node-negative patients ranged from 0% to 11.4% in the 13 included studies. Based on fixed-effects modeling, the rate of involvement was 2.53% (95% CI, 1.64-3.55%), according to the published report.
The rate of skip metastasis was “extremely low,” wrote Dr. Warshavsky and coauthors. Rates ranged from 0% to 5.50%, with a fixed-effects model of 0.50% (95% CI, 0.09%-1.11%).
Cases involving higher levels of the neck did not impact the rate of level IV metastasis, results of a subgroup analysis found. Likewise, an analysis based on T stage showed that rates of level 4 involvement were comparable and low for T stages I-II and III-IV.
These findings are limited, however, not only by the retrospective nature of this study, but also by the fact that many studies reported limited data, hampering the investigators’ ability to run statistics and perform subgroup analyses.
“Unfortunately, data in almost all of the analyzed articles failed to report the relations between the primary tumor site and the neck levels involved by metastatic tumor,” they wrote. “Only primary lesions of the tongue could be accurately assessed.”
Dr. Warshavsky and coauthors reported no conflicts of interest related to the research.
SOURCE: Warshavsky A et al. JAMA Otolaryngol Head Neck Surg. 2019 May 9. doi: 10.1001/jamaoto.2019.0784.
Although this meta-analysis shows that the risk of level IV involvement is less than 5% in patients with clinically node-negative (cN0) oral cavity cancers, going beyond standard supraomohyoid neck dissection (SOHND) may still be warranted for specific patients.
While the authors conclude that elective treatment of level IV is not required in patients with cN0 oral cavity cancer, there are two situations in which clinicians should consider adding level IV to standard SOHND.
The first is when a patient has gross macroscopic disease in upper levels, particularly level III. Most studies in the meta-analysis had insufficient data to determine whether involvement of upper levels increased risk of level IV involvement. When encountering gross disease during an elective neck dissection, some researchers have recommended including level IV and V.
The second scenario is when a posterolateral oral tongue cancer is near or at the tongue base, since oropharyngeal cancers are known to drain to levels II-IV.
The decision to make exceptions in these two situations should be based on the combination of clinical judgment and evidence-based medicine in certain situations. That said, for most patients with cNO oral cavity cancer, SOHND is enough.
Arun Sharma, MD, MS , is with the division of otolaryngology–head and neck surgery at Southern Illinois University, Springfield. He had no conflict of interest related to his editorial, which appears in JAMA Otolaryngology–Head & Neck Surgery .
Although this meta-analysis shows that the risk of level IV involvement is less than 5% in patients with clinically node-negative (cN0) oral cavity cancers, going beyond standard supraomohyoid neck dissection (SOHND) may still be warranted for specific patients.
While the authors conclude that elective treatment of level IV is not required in patients with cN0 oral cavity cancer, there are two situations in which clinicians should consider adding level IV to standard SOHND.
The first is when a patient has gross macroscopic disease in upper levels, particularly level III. Most studies in the meta-analysis had insufficient data to determine whether involvement of upper levels increased risk of level IV involvement. When encountering gross disease during an elective neck dissection, some researchers have recommended including level IV and V.
The second scenario is when a posterolateral oral tongue cancer is near or at the tongue base, since oropharyngeal cancers are known to drain to levels II-IV.
The decision to make exceptions in these two situations should be based on the combination of clinical judgment and evidence-based medicine in certain situations. That said, for most patients with cNO oral cavity cancer, SOHND is enough.
Arun Sharma, MD, MS , is with the division of otolaryngology–head and neck surgery at Southern Illinois University, Springfield. He had no conflict of interest related to his editorial, which appears in JAMA Otolaryngology–Head & Neck Surgery .
Although this meta-analysis shows that the risk of level IV involvement is less than 5% in patients with clinically node-negative (cN0) oral cavity cancers, going beyond standard supraomohyoid neck dissection (SOHND) may still be warranted for specific patients.
While the authors conclude that elective treatment of level IV is not required in patients with cN0 oral cavity cancer, there are two situations in which clinicians should consider adding level IV to standard SOHND.
The first is when a patient has gross macroscopic disease in upper levels, particularly level III. Most studies in the meta-analysis had insufficient data to determine whether involvement of upper levels increased risk of level IV involvement. When encountering gross disease during an elective neck dissection, some researchers have recommended including level IV and V.
The second scenario is when a posterolateral oral tongue cancer is near or at the tongue base, since oropharyngeal cancers are known to drain to levels II-IV.
The decision to make exceptions in these two situations should be based on the combination of clinical judgment and evidence-based medicine in certain situations. That said, for most patients with cNO oral cavity cancer, SOHND is enough.
Arun Sharma, MD, MS , is with the division of otolaryngology–head and neck surgery at Southern Illinois University, Springfield. He had no conflict of interest related to his editorial, which appears in JAMA Otolaryngology–Head & Neck Surgery .
In patients with clinically node-negative oral cavity cancers, the rate of skip metastasis to neck level IV is extremely low, according to authors of a recent meta-analysis.
The rate of level IV involvement was about 2.5%, and the rate of skip metastasis was 0.5% in the analysis, which comprised 11 retrospective studies and 2 randomized clinical trials including a total of 1,359 patients with clinically node-negative oral cavity squamous cell carcinomas.
Encountering a suspected positive lymph node during neck dissection does not appear to be an indicator of high rates of level IV involvement, according to Anton Warshavsky, MD, and colleagues in the department of otolaryngology–head and neck surgery and maxillofacial surgery at Tel Aviv Sourasky Medical Center, Israel.
“Supraomohyoid neck dissection [SOHND] is adequate for this subset of patients,” Dr. Warshavsky and coauthors wrote in a report on the study that appears in JAMA Otolaryngology–Head & Neck Surgery.
SOHND, a type of selective neck dissection, refers to removal of lymph nodes in levels I-III. This approach is now frequently used in managing clinically node-negative oral cavity squamous cell carcinoma and provides control rates similar to those associated with more extensive neck dissections, Dr. Warshavsky and colleagues wrote.
However, concern regarding the risk of skip metastases, or involvement of neck level IV without involvement of lower levels, has stirred controversy. SOHND might not be adequate in these patients because of the possibility of occult metastasis to neck level IV.
Accordingly, Dr. Warshavsky and colleagues combed the available medical literature to find relevant articles for a meta-analysis to better characterize the rate of skip metastasis to level IV in patients who had undergone neck dissection.
Level IV involvement rates in clinically node-negative patients ranged from 0% to 11.4% in the 13 included studies. Based on fixed-effects modeling, the rate of involvement was 2.53% (95% CI, 1.64-3.55%), according to the published report.
The rate of skip metastasis was “extremely low,” wrote Dr. Warshavsky and coauthors. Rates ranged from 0% to 5.50%, with a fixed-effects model of 0.50% (95% CI, 0.09%-1.11%).
Cases involving higher levels of the neck did not impact the rate of level IV metastasis, results of a subgroup analysis found. Likewise, an analysis based on T stage showed that rates of level 4 involvement were comparable and low for T stages I-II and III-IV.
These findings are limited, however, not only by the retrospective nature of this study, but also by the fact that many studies reported limited data, hampering the investigators’ ability to run statistics and perform subgroup analyses.
“Unfortunately, data in almost all of the analyzed articles failed to report the relations between the primary tumor site and the neck levels involved by metastatic tumor,” they wrote. “Only primary lesions of the tongue could be accurately assessed.”
Dr. Warshavsky and coauthors reported no conflicts of interest related to the research.
SOURCE: Warshavsky A et al. JAMA Otolaryngol Head Neck Surg. 2019 May 9. doi: 10.1001/jamaoto.2019.0784.
In patients with clinically node-negative oral cavity cancers, the rate of skip metastasis to neck level IV is extremely low, according to authors of a recent meta-analysis.
The rate of level IV involvement was about 2.5%, and the rate of skip metastasis was 0.5% in the analysis, which comprised 11 retrospective studies and 2 randomized clinical trials including a total of 1,359 patients with clinically node-negative oral cavity squamous cell carcinomas.
Encountering a suspected positive lymph node during neck dissection does not appear to be an indicator of high rates of level IV involvement, according to Anton Warshavsky, MD, and colleagues in the department of otolaryngology–head and neck surgery and maxillofacial surgery at Tel Aviv Sourasky Medical Center, Israel.
“Supraomohyoid neck dissection [SOHND] is adequate for this subset of patients,” Dr. Warshavsky and coauthors wrote in a report on the study that appears in JAMA Otolaryngology–Head & Neck Surgery.
SOHND, a type of selective neck dissection, refers to removal of lymph nodes in levels I-III. This approach is now frequently used in managing clinically node-negative oral cavity squamous cell carcinoma and provides control rates similar to those associated with more extensive neck dissections, Dr. Warshavsky and colleagues wrote.
However, concern regarding the risk of skip metastases, or involvement of neck level IV without involvement of lower levels, has stirred controversy. SOHND might not be adequate in these patients because of the possibility of occult metastasis to neck level IV.
Accordingly, Dr. Warshavsky and colleagues combed the available medical literature to find relevant articles for a meta-analysis to better characterize the rate of skip metastasis to level IV in patients who had undergone neck dissection.
Level IV involvement rates in clinically node-negative patients ranged from 0% to 11.4% in the 13 included studies. Based on fixed-effects modeling, the rate of involvement was 2.53% (95% CI, 1.64-3.55%), according to the published report.
The rate of skip metastasis was “extremely low,” wrote Dr. Warshavsky and coauthors. Rates ranged from 0% to 5.50%, with a fixed-effects model of 0.50% (95% CI, 0.09%-1.11%).
Cases involving higher levels of the neck did not impact the rate of level IV metastasis, results of a subgroup analysis found. Likewise, an analysis based on T stage showed that rates of level 4 involvement were comparable and low for T stages I-II and III-IV.
These findings are limited, however, not only by the retrospective nature of this study, but also by the fact that many studies reported limited data, hampering the investigators’ ability to run statistics and perform subgroup analyses.
“Unfortunately, data in almost all of the analyzed articles failed to report the relations between the primary tumor site and the neck levels involved by metastatic tumor,” they wrote. “Only primary lesions of the tongue could be accurately assessed.”
Dr. Warshavsky and coauthors reported no conflicts of interest related to the research.
SOURCE: Warshavsky A et al. JAMA Otolaryngol Head Neck Surg. 2019 May 9. doi: 10.1001/jamaoto.2019.0784.
FROM JAMA OTOLARYNGOLOGY–HEAD & NECK SURGERY
Key clinical point: In patients with clinically node-negative oral cavity cancers, rates of skip metastasis to neck level IV are extremely low, meaning that supraomohyoid neck dissection is likely sufficient for most cases.
Major finding: The rate of level IV involvement was about 2.5%, and the rate of skip metastasis was 0.5%.
Study details: A meta-analysis of 11 retrospective studies and 2 randomized clinical trials, including a total of 1,359 patients who had undergone neck dissection.
Disclosures: The study authors reported no conflicts of interest.
Source: Warshavsky A et al. JAMA Otolaryngol Head Neck Surg. 2019 May 9. doi: 10.1001/jamaoto.2019.0784.
Smoking rates remain steady among the poor
While an increasing number of U.S. citizens are saying no to cigarettes, a recent study shows.
The odds of current smoking, versus never smoking, declined significantly during 2008-2017 for individuals with none of six disadvantages tied to cigarette use, including disability, unemployment, poverty, low education, psychological distress, and heavy alcohol intake, according to researchers.
Individuals with one or two of those disadvantages have also been cutting back, the data suggest. But, by contrast, odds of current versus never smoking did not significantly change for those with three or more disadvantages, according to Adam M. Leventhal, PhD, of the University of Southern California, Los Angeles, and coinvestigators.
“How this pattern can inform a cohesive policy agenda is unknown, but it is clear from these findings that the crux of the recently expanding tobacco-related health disparity problem in the United States is not tied to groups facing merely a single form of disadvantage,” Dr. Leventhal and coauthors wrote in a report on the study in JAMA Internal Medicine.
The cross-sectional analysis by Dr. Leventhal and colleagues was based on National Health Interview Survey (NHIS) data from 2008-2017 including more than 278,000 respondents aged 25 years or older.
A snapshot of that 10-year period showed that current smoking prevalence was successively higher depending on the number of socioeconomic or health-related disadvantages.
The mean prevalence of current smoking over that entire time period was just 13.8% for people with zero of the six disadvantages, 21.4% for those with one disadvantage, and so on, up to 58.2% for those with all six disadvantages, according to data in the published report.
Encouragingly, overall smoking prevalence fell from 20.8% in 2008-2009 to 15.8% in 2016-2017, the researchers found. However, the decreasing trend was not apparent for individuals with many disadvantages.
The odds ratio for change in odds of smoking per year was 0.951 (95% confidence interval, 0.944-0.958) for those with zero disadvantages, 0.96 (95% CI, 0.95-0.97) for one disadvantage, and 0.98 (95% CI, 0.97-0.99) for two, all representing significant annual reductions in current versus never smoking, investigators said. By contrast, no such significant changes were apparent for those with three, four, five, or six such disadvantages.
Tobacco control or regulatory policies that consider these disadvantages separately may be overlooking a “broader pattern” showing that the cumulative number of disadvantages correlates with the magnitude of disparity, wrote Dr. Leventhal and colleagues in their report.
“Successful prevention of smoking initiation and promotion of smoking cessation in multi-disadvantaged populations would substantially reduce the smoking-related public health burden in the United States,” they concluded.
Dr. Leventhal and colleagues reported no conflicts related to their research, which was supported in part by a Tobacco Centers of Regulatory Science award from the National Cancer Institute and the Food and Drug Administration, among other sources.
SOURCE: Leventhal AM et al. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0192.
While an increasing number of U.S. citizens are saying no to cigarettes, a recent study shows.
The odds of current smoking, versus never smoking, declined significantly during 2008-2017 for individuals with none of six disadvantages tied to cigarette use, including disability, unemployment, poverty, low education, psychological distress, and heavy alcohol intake, according to researchers.
Individuals with one or two of those disadvantages have also been cutting back, the data suggest. But, by contrast, odds of current versus never smoking did not significantly change for those with three or more disadvantages, according to Adam M. Leventhal, PhD, of the University of Southern California, Los Angeles, and coinvestigators.
“How this pattern can inform a cohesive policy agenda is unknown, but it is clear from these findings that the crux of the recently expanding tobacco-related health disparity problem in the United States is not tied to groups facing merely a single form of disadvantage,” Dr. Leventhal and coauthors wrote in a report on the study in JAMA Internal Medicine.
The cross-sectional analysis by Dr. Leventhal and colleagues was based on National Health Interview Survey (NHIS) data from 2008-2017 including more than 278,000 respondents aged 25 years or older.
A snapshot of that 10-year period showed that current smoking prevalence was successively higher depending on the number of socioeconomic or health-related disadvantages.
The mean prevalence of current smoking over that entire time period was just 13.8% for people with zero of the six disadvantages, 21.4% for those with one disadvantage, and so on, up to 58.2% for those with all six disadvantages, according to data in the published report.
Encouragingly, overall smoking prevalence fell from 20.8% in 2008-2009 to 15.8% in 2016-2017, the researchers found. However, the decreasing trend was not apparent for individuals with many disadvantages.
The odds ratio for change in odds of smoking per year was 0.951 (95% confidence interval, 0.944-0.958) for those with zero disadvantages, 0.96 (95% CI, 0.95-0.97) for one disadvantage, and 0.98 (95% CI, 0.97-0.99) for two, all representing significant annual reductions in current versus never smoking, investigators said. By contrast, no such significant changes were apparent for those with three, four, five, or six such disadvantages.
Tobacco control or regulatory policies that consider these disadvantages separately may be overlooking a “broader pattern” showing that the cumulative number of disadvantages correlates with the magnitude of disparity, wrote Dr. Leventhal and colleagues in their report.
“Successful prevention of smoking initiation and promotion of smoking cessation in multi-disadvantaged populations would substantially reduce the smoking-related public health burden in the United States,” they concluded.
Dr. Leventhal and colleagues reported no conflicts related to their research, which was supported in part by a Tobacco Centers of Regulatory Science award from the National Cancer Institute and the Food and Drug Administration, among other sources.
SOURCE: Leventhal AM et al. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0192.
While an increasing number of U.S. citizens are saying no to cigarettes, a recent study shows.
The odds of current smoking, versus never smoking, declined significantly during 2008-2017 for individuals with none of six disadvantages tied to cigarette use, including disability, unemployment, poverty, low education, psychological distress, and heavy alcohol intake, according to researchers.
Individuals with one or two of those disadvantages have also been cutting back, the data suggest. But, by contrast, odds of current versus never smoking did not significantly change for those with three or more disadvantages, according to Adam M. Leventhal, PhD, of the University of Southern California, Los Angeles, and coinvestigators.
“How this pattern can inform a cohesive policy agenda is unknown, but it is clear from these findings that the crux of the recently expanding tobacco-related health disparity problem in the United States is not tied to groups facing merely a single form of disadvantage,” Dr. Leventhal and coauthors wrote in a report on the study in JAMA Internal Medicine.
The cross-sectional analysis by Dr. Leventhal and colleagues was based on National Health Interview Survey (NHIS) data from 2008-2017 including more than 278,000 respondents aged 25 years or older.
A snapshot of that 10-year period showed that current smoking prevalence was successively higher depending on the number of socioeconomic or health-related disadvantages.
The mean prevalence of current smoking over that entire time period was just 13.8% for people with zero of the six disadvantages, 21.4% for those with one disadvantage, and so on, up to 58.2% for those with all six disadvantages, according to data in the published report.
Encouragingly, overall smoking prevalence fell from 20.8% in 2008-2009 to 15.8% in 2016-2017, the researchers found. However, the decreasing trend was not apparent for individuals with many disadvantages.
The odds ratio for change in odds of smoking per year was 0.951 (95% confidence interval, 0.944-0.958) for those with zero disadvantages, 0.96 (95% CI, 0.95-0.97) for one disadvantage, and 0.98 (95% CI, 0.97-0.99) for two, all representing significant annual reductions in current versus never smoking, investigators said. By contrast, no such significant changes were apparent for those with three, four, five, or six such disadvantages.
Tobacco control or regulatory policies that consider these disadvantages separately may be overlooking a “broader pattern” showing that the cumulative number of disadvantages correlates with the magnitude of disparity, wrote Dr. Leventhal and colleagues in their report.
“Successful prevention of smoking initiation and promotion of smoking cessation in multi-disadvantaged populations would substantially reduce the smoking-related public health burden in the United States,” they concluded.
Dr. Leventhal and colleagues reported no conflicts related to their research, which was supported in part by a Tobacco Centers of Regulatory Science award from the National Cancer Institute and the Food and Drug Administration, among other sources.
SOURCE: Leventhal AM et al. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0192.
FROM JAMA INTERNAL MEDICINE
Key clinical point: Current U.S. smoking rates have not declined among individuals with multiple socioeconomic or health-related disadvantages.
Major finding: The odds ratio for change in odds of smoking per year was 0.951 for individuals with zero disadvantages, 0.96 for one disadvantage, and 0.97-0.99 for two, with no significant annual reductions in those with three or more disadvantages.
Study details: Cross-sectional analysis of 278,048 respondents aged 25 years or older in the National Health Interview Survey during 2008-2017.
Disclosures: Authors reported no conflicts of interest related to the study, which was supported in part by a Tobacco Centers of Regulatory Science award from the National Cancer Institute and the Food and Drug Administration, among other sources.
Source: Leventhal AM et al. JAMA Intern Med. 2019 Apr 22. doi: 10.1001/jamainternmed.2019.0192.
Do some EGFR mutation subtypes benefit from immune checkpoint blockade?
Although epidermal growth factor receptor–mutant lung cancers generally don’t benefit from checkpoint inhibitors, there may be some subtypes that do respond, results of a large, multi-institution analysis suggest.
Compared with wild-type lung cancer cases, tumors with epidermal growth factor receptor (EGFR) exon 19 deletion did indeed have worse outcomes after progressive death-1/progressive death–ligand 1 (PD-1/PD-L1) blockade; however, tumors harboring EGFR L858R mutations had comparable response rates and overall survival.
These findings don’t change clinical practice, but do serve as a “foundation” for more research into which patients with EGFR-mutant disease might benefit from immunotherapy, according to Katherine Hastings, PhD, of Yale University, New Haven, Conn., and associates.
“We unequivocally support the guidance that EGFR TKIs should be the preferred first-line treatment option for patients with EGFR-mutant lung cancer,” Dr. Hastings and coauthors wrote in Annals of Oncology.
To date, clinical investigations of immune checkpoint inhibitors in patients with EGFR-mutant lung cancers have largely been discouraging, the authors wrote. However, there have been some exceptions, including a phase 2 study where third-line durvalumab showed activity in some patients with EGFR-positive, PD-L1-expressing advanced non–small cell lung cancer (NSCLC).
Accordingly, the investigators sought to determine whether specific molecular features made a difference. They looked at a total of 171 EGFR-mutant lung cancers that had been treated with PD-1/PD-L1 inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 inhibitor.
In their analysis, they drilled down on the most common EGFR tyrosine kinase inhibitor–sensitizing alleles: EGFR exon 19 deletions, which represented 76 cases, and EGFR L858R, which represented 44 cases. For comparison, they looked at a cohort of 212 patients with EGFR wild-type NSCLC who had also been treated with immune checkpoint inhibitors.
EGFR exon 19 deletion cases had a significantly lower overall response rate versus EGFR wild-type tumors, at 7% versus 22%, respectively (P = .002), the investigators found. Likewise, overall survival was significantly reduced, with a hazard ratio of 0.69 (95% confidence interval, 0.493-0.965; P = .03).
By contrast, EGFR L858R tumors had similar response rates versus EGFR wild type, at 16% and 22%, respectively (P = .42); overall survival also was similar, with a hazard ratio of 0.917 (95% CI, 0.597-1.409; P = .69).
Of note, progression-free survival was reduced in both EGFR L858R and EGFR exon 19 deletion cases as compared with EGFR wild-type cases, though the investigators wrote that discrepancy might be related to variations in scanning intervals between different institutions that contributed cases to the study.
“Overall, these data suggest that patients with EGFR exon 19–mutant tumors, in particular, have a significantly reduced benefit upon treatment with immune checkpoint inhibitors,” the authors noted.
In a separate but related analysis of 383 patients with EGFR-mutant lung cancer, tumor mutation burden was lower in EGFR exon 19 deletion cases as compared with the EGFR L858R cases. That finding lined up with the immunotherapy response data, the investigators wrote, though it’s unclear what might be driving the differences in tumor burden between these two groups.
There were no differences in response to immune checkpoint blockade based on whether or not tumors harbored the EGFR T790M mutation, the investigators added. Similarly, PD-L1 expression did not impact response.
The study authors reported disclosures related to Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Daiichi, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche, and Takeda, among others.
SOURCE: Hastings K et al. Ann Oncol. 2019 May 14. doi: 10.1093/annonc/mdz141.
Although epidermal growth factor receptor–mutant lung cancers generally don’t benefit from checkpoint inhibitors, there may be some subtypes that do respond, results of a large, multi-institution analysis suggest.
Compared with wild-type lung cancer cases, tumors with epidermal growth factor receptor (EGFR) exon 19 deletion did indeed have worse outcomes after progressive death-1/progressive death–ligand 1 (PD-1/PD-L1) blockade; however, tumors harboring EGFR L858R mutations had comparable response rates and overall survival.
These findings don’t change clinical practice, but do serve as a “foundation” for more research into which patients with EGFR-mutant disease might benefit from immunotherapy, according to Katherine Hastings, PhD, of Yale University, New Haven, Conn., and associates.
“We unequivocally support the guidance that EGFR TKIs should be the preferred first-line treatment option for patients with EGFR-mutant lung cancer,” Dr. Hastings and coauthors wrote in Annals of Oncology.
To date, clinical investigations of immune checkpoint inhibitors in patients with EGFR-mutant lung cancers have largely been discouraging, the authors wrote. However, there have been some exceptions, including a phase 2 study where third-line durvalumab showed activity in some patients with EGFR-positive, PD-L1-expressing advanced non–small cell lung cancer (NSCLC).
Accordingly, the investigators sought to determine whether specific molecular features made a difference. They looked at a total of 171 EGFR-mutant lung cancers that had been treated with PD-1/PD-L1 inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 inhibitor.
In their analysis, they drilled down on the most common EGFR tyrosine kinase inhibitor–sensitizing alleles: EGFR exon 19 deletions, which represented 76 cases, and EGFR L858R, which represented 44 cases. For comparison, they looked at a cohort of 212 patients with EGFR wild-type NSCLC who had also been treated with immune checkpoint inhibitors.
EGFR exon 19 deletion cases had a significantly lower overall response rate versus EGFR wild-type tumors, at 7% versus 22%, respectively (P = .002), the investigators found. Likewise, overall survival was significantly reduced, with a hazard ratio of 0.69 (95% confidence interval, 0.493-0.965; P = .03).
By contrast, EGFR L858R tumors had similar response rates versus EGFR wild type, at 16% and 22%, respectively (P = .42); overall survival also was similar, with a hazard ratio of 0.917 (95% CI, 0.597-1.409; P = .69).
Of note, progression-free survival was reduced in both EGFR L858R and EGFR exon 19 deletion cases as compared with EGFR wild-type cases, though the investigators wrote that discrepancy might be related to variations in scanning intervals between different institutions that contributed cases to the study.
“Overall, these data suggest that patients with EGFR exon 19–mutant tumors, in particular, have a significantly reduced benefit upon treatment with immune checkpoint inhibitors,” the authors noted.
In a separate but related analysis of 383 patients with EGFR-mutant lung cancer, tumor mutation burden was lower in EGFR exon 19 deletion cases as compared with the EGFR L858R cases. That finding lined up with the immunotherapy response data, the investigators wrote, though it’s unclear what might be driving the differences in tumor burden between these two groups.
There were no differences in response to immune checkpoint blockade based on whether or not tumors harbored the EGFR T790M mutation, the investigators added. Similarly, PD-L1 expression did not impact response.
The study authors reported disclosures related to Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Daiichi, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche, and Takeda, among others.
SOURCE: Hastings K et al. Ann Oncol. 2019 May 14. doi: 10.1093/annonc/mdz141.
Although epidermal growth factor receptor–mutant lung cancers generally don’t benefit from checkpoint inhibitors, there may be some subtypes that do respond, results of a large, multi-institution analysis suggest.
Compared with wild-type lung cancer cases, tumors with epidermal growth factor receptor (EGFR) exon 19 deletion did indeed have worse outcomes after progressive death-1/progressive death–ligand 1 (PD-1/PD-L1) blockade; however, tumors harboring EGFR L858R mutations had comparable response rates and overall survival.
These findings don’t change clinical practice, but do serve as a “foundation” for more research into which patients with EGFR-mutant disease might benefit from immunotherapy, according to Katherine Hastings, PhD, of Yale University, New Haven, Conn., and associates.
“We unequivocally support the guidance that EGFR TKIs should be the preferred first-line treatment option for patients with EGFR-mutant lung cancer,” Dr. Hastings and coauthors wrote in Annals of Oncology.
To date, clinical investigations of immune checkpoint inhibitors in patients with EGFR-mutant lung cancers have largely been discouraging, the authors wrote. However, there have been some exceptions, including a phase 2 study where third-line durvalumab showed activity in some patients with EGFR-positive, PD-L1-expressing advanced non–small cell lung cancer (NSCLC).
Accordingly, the investigators sought to determine whether specific molecular features made a difference. They looked at a total of 171 EGFR-mutant lung cancers that had been treated with PD-1/PD-L1 inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 inhibitor.
In their analysis, they drilled down on the most common EGFR tyrosine kinase inhibitor–sensitizing alleles: EGFR exon 19 deletions, which represented 76 cases, and EGFR L858R, which represented 44 cases. For comparison, they looked at a cohort of 212 patients with EGFR wild-type NSCLC who had also been treated with immune checkpoint inhibitors.
EGFR exon 19 deletion cases had a significantly lower overall response rate versus EGFR wild-type tumors, at 7% versus 22%, respectively (P = .002), the investigators found. Likewise, overall survival was significantly reduced, with a hazard ratio of 0.69 (95% confidence interval, 0.493-0.965; P = .03).
By contrast, EGFR L858R tumors had similar response rates versus EGFR wild type, at 16% and 22%, respectively (P = .42); overall survival also was similar, with a hazard ratio of 0.917 (95% CI, 0.597-1.409; P = .69).
Of note, progression-free survival was reduced in both EGFR L858R and EGFR exon 19 deletion cases as compared with EGFR wild-type cases, though the investigators wrote that discrepancy might be related to variations in scanning intervals between different institutions that contributed cases to the study.
“Overall, these data suggest that patients with EGFR exon 19–mutant tumors, in particular, have a significantly reduced benefit upon treatment with immune checkpoint inhibitors,” the authors noted.
In a separate but related analysis of 383 patients with EGFR-mutant lung cancer, tumor mutation burden was lower in EGFR exon 19 deletion cases as compared with the EGFR L858R cases. That finding lined up with the immunotherapy response data, the investigators wrote, though it’s unclear what might be driving the differences in tumor burden between these two groups.
There were no differences in response to immune checkpoint blockade based on whether or not tumors harbored the EGFR T790M mutation, the investigators added. Similarly, PD-L1 expression did not impact response.
The study authors reported disclosures related to Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Daiichi, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche, and Takeda, among others.
SOURCE: Hastings K et al. Ann Oncol. 2019 May 14. doi: 10.1093/annonc/mdz141.
FROM ANNALS OF ONCOLOGY
More than 40% of U.K. physicians report binge drinking
Many doctors say they cope with job-related stress by drinking alcohol or taking drugs
Occupational distress among physicians is tied to increased odds of substance use, sleep disturbance, binge eating, and poor health in general, a cross-sectional study of 417 U.K. doctors shows.
Burned-out or depressed doctors had higher risks of those health problems regardless of whether or not they worked in a hospital setting, according to Asta Medisauskaite, PhD, of University College London and Caroline Kamau, PhD, of the University of London. The study was published in BMJ Open.
The investigators asked the participants to answer a battery of validated questionnaires online, including the Alcohol Use Disorders Identification Test, the Eating Disorder Diagnostic Scale, and the Insomnia Severity Index.
The odds of many health problems were increased among the physicians with emotional exhaustion, as indicated by the Maslach Burnout Inventory, as was also the case with psychiatric disorders, according to the General Health Questionnaire-12, which investigators noted has been used extensively to examine medical doctors and other working populations.
Sleep disturbances were, for example, more likely in physicians with burnout or psychiatric morbidity, with odds ratios ranging from 1.344 to 3.826, the investigators reported. Likewise, these indicators of occupational distress increased the risk of suffering from frequent poor health, with odds ratios from 1.050 to 3.544, and of binge eating, with odds ratios from 1.311 to 1.841, Dr. Medisauskaite and Dr. Kamau reported.
Distressed doctors more often used alcohol, according to the researchers, who said that they found a higher risk of alcohol dependence (odds ratio, 6.165) among physicians reporting that they used substances to feel better or cope with stress. Those doctors also had higher risk of binge drinking, drinking larger quantities, and using alcohol more often, the data show. In fact, 44% of the physicians reported binge drinking, and 5% met the criteria for alcohol dependence, Dr. Medisauskaite and Dr. Kamau wrote. Binge drinking was defined as consuming more than six drinks on a single occasion.
Previous studies have indicated that occupational distress among physicians has negative effects on quality of care and patient safety, the authors noted. This latest cross-sectional study builds on those findings by showing that occupational distress increases risk of health problems among doctors. “The impact of occupational distress or ill health could increase levels of sickness-absence among doctors, thus reducing patient safety because of understaffing,” Dr. Medisauskaite and Dr. Kamau wrote.
Similarly, physicians with sleep problems or substance use related to occupational distress could perform poorly on the job because of being groggy, intoxicated, or hung over, they said.
“We recommend that doctors’ mentors, supervisors, peers, and occupational health support services recognize and act on (1) the prevalence of occupational distress and health problems among doctors; (2) the possibility that occupational distress raises the risk of several health problems; and (3) the need to provide early interventions,” Dr. Medisauskaite and Dr. Kamau wrote. Such interventions could help prevent physicians who are experiencing occupational distress from suffering the long-term health effects from sleep disturbances, binge drinking and binge eating, and ill health, they suggested.
One limitation cited was the study’s cross-sectional design, which makes it impossible to draw conclusions about causation. The researchers also conceded that some participants might not have been comfortable answering questions about illicit use of drugs or alcohol. Nevertheless, they said,
Dr. Medisauskaite and Dr. Kamau declared no competing interests related to the study.
SOURCE: Medisauskaite A, Kamau C. BMJ Open. 2019 May 15. doi: 10.1136/bmjopen-2018-027362.
Many doctors say they cope with job-related stress by drinking alcohol or taking drugs
Many doctors say they cope with job-related stress by drinking alcohol or taking drugs
Occupational distress among physicians is tied to increased odds of substance use, sleep disturbance, binge eating, and poor health in general, a cross-sectional study of 417 U.K. doctors shows.
Burned-out or depressed doctors had higher risks of those health problems regardless of whether or not they worked in a hospital setting, according to Asta Medisauskaite, PhD, of University College London and Caroline Kamau, PhD, of the University of London. The study was published in BMJ Open.
The investigators asked the participants to answer a battery of validated questionnaires online, including the Alcohol Use Disorders Identification Test, the Eating Disorder Diagnostic Scale, and the Insomnia Severity Index.
The odds of many health problems were increased among the physicians with emotional exhaustion, as indicated by the Maslach Burnout Inventory, as was also the case with psychiatric disorders, according to the General Health Questionnaire-12, which investigators noted has been used extensively to examine medical doctors and other working populations.
Sleep disturbances were, for example, more likely in physicians with burnout or psychiatric morbidity, with odds ratios ranging from 1.344 to 3.826, the investigators reported. Likewise, these indicators of occupational distress increased the risk of suffering from frequent poor health, with odds ratios from 1.050 to 3.544, and of binge eating, with odds ratios from 1.311 to 1.841, Dr. Medisauskaite and Dr. Kamau reported.
Distressed doctors more often used alcohol, according to the researchers, who said that they found a higher risk of alcohol dependence (odds ratio, 6.165) among physicians reporting that they used substances to feel better or cope with stress. Those doctors also had higher risk of binge drinking, drinking larger quantities, and using alcohol more often, the data show. In fact, 44% of the physicians reported binge drinking, and 5% met the criteria for alcohol dependence, Dr. Medisauskaite and Dr. Kamau wrote. Binge drinking was defined as consuming more than six drinks on a single occasion.
Previous studies have indicated that occupational distress among physicians has negative effects on quality of care and patient safety, the authors noted. This latest cross-sectional study builds on those findings by showing that occupational distress increases risk of health problems among doctors. “The impact of occupational distress or ill health could increase levels of sickness-absence among doctors, thus reducing patient safety because of understaffing,” Dr. Medisauskaite and Dr. Kamau wrote.
Similarly, physicians with sleep problems or substance use related to occupational distress could perform poorly on the job because of being groggy, intoxicated, or hung over, they said.
“We recommend that doctors’ mentors, supervisors, peers, and occupational health support services recognize and act on (1) the prevalence of occupational distress and health problems among doctors; (2) the possibility that occupational distress raises the risk of several health problems; and (3) the need to provide early interventions,” Dr. Medisauskaite and Dr. Kamau wrote. Such interventions could help prevent physicians who are experiencing occupational distress from suffering the long-term health effects from sleep disturbances, binge drinking and binge eating, and ill health, they suggested.
One limitation cited was the study’s cross-sectional design, which makes it impossible to draw conclusions about causation. The researchers also conceded that some participants might not have been comfortable answering questions about illicit use of drugs or alcohol. Nevertheless, they said,
Dr. Medisauskaite and Dr. Kamau declared no competing interests related to the study.
SOURCE: Medisauskaite A, Kamau C. BMJ Open. 2019 May 15. doi: 10.1136/bmjopen-2018-027362.
Occupational distress among physicians is tied to increased odds of substance use, sleep disturbance, binge eating, and poor health in general, a cross-sectional study of 417 U.K. doctors shows.
Burned-out or depressed doctors had higher risks of those health problems regardless of whether or not they worked in a hospital setting, according to Asta Medisauskaite, PhD, of University College London and Caroline Kamau, PhD, of the University of London. The study was published in BMJ Open.
The investigators asked the participants to answer a battery of validated questionnaires online, including the Alcohol Use Disorders Identification Test, the Eating Disorder Diagnostic Scale, and the Insomnia Severity Index.
The odds of many health problems were increased among the physicians with emotional exhaustion, as indicated by the Maslach Burnout Inventory, as was also the case with psychiatric disorders, according to the General Health Questionnaire-12, which investigators noted has been used extensively to examine medical doctors and other working populations.
Sleep disturbances were, for example, more likely in physicians with burnout or psychiatric morbidity, with odds ratios ranging from 1.344 to 3.826, the investigators reported. Likewise, these indicators of occupational distress increased the risk of suffering from frequent poor health, with odds ratios from 1.050 to 3.544, and of binge eating, with odds ratios from 1.311 to 1.841, Dr. Medisauskaite and Dr. Kamau reported.
Distressed doctors more often used alcohol, according to the researchers, who said that they found a higher risk of alcohol dependence (odds ratio, 6.165) among physicians reporting that they used substances to feel better or cope with stress. Those doctors also had higher risk of binge drinking, drinking larger quantities, and using alcohol more often, the data show. In fact, 44% of the physicians reported binge drinking, and 5% met the criteria for alcohol dependence, Dr. Medisauskaite and Dr. Kamau wrote. Binge drinking was defined as consuming more than six drinks on a single occasion.
Previous studies have indicated that occupational distress among physicians has negative effects on quality of care and patient safety, the authors noted. This latest cross-sectional study builds on those findings by showing that occupational distress increases risk of health problems among doctors. “The impact of occupational distress or ill health could increase levels of sickness-absence among doctors, thus reducing patient safety because of understaffing,” Dr. Medisauskaite and Dr. Kamau wrote.
Similarly, physicians with sleep problems or substance use related to occupational distress could perform poorly on the job because of being groggy, intoxicated, or hung over, they said.
“We recommend that doctors’ mentors, supervisors, peers, and occupational health support services recognize and act on (1) the prevalence of occupational distress and health problems among doctors; (2) the possibility that occupational distress raises the risk of several health problems; and (3) the need to provide early interventions,” Dr. Medisauskaite and Dr. Kamau wrote. Such interventions could help prevent physicians who are experiencing occupational distress from suffering the long-term health effects from sleep disturbances, binge drinking and binge eating, and ill health, they suggested.
One limitation cited was the study’s cross-sectional design, which makes it impossible to draw conclusions about causation. The researchers also conceded that some participants might not have been comfortable answering questions about illicit use of drugs or alcohol. Nevertheless, they said,
Dr. Medisauskaite and Dr. Kamau declared no competing interests related to the study.
SOURCE: Medisauskaite A, Kamau C. BMJ Open. 2019 May 15. doi: 10.1136/bmjopen-2018-027362.
FROM BMJ OPEN
Key clinical point: Occupational distress increased the odds of substance use, sleep disturbance, binge eating, and poor health among medical doctors in the United Kingdom.
Major finding: Distressed medical doctors had a higher risk of binge drinking. In fact, 44% reported binge drinking, defined as consuming more than six drinks on a single occasion.
Study details: A U.K. cross-sectional study of 417 doctors who answered a series of validated health-related questionnaires online.
Disclosures: The authors declared no competing interests related to the study.
Source: Medisauskaite A, Kamau C. BMJ Open. 2019 May 15. doi: 10.1136/bmjopen-2018-027362.
Evobrutinib demonstrates efficacy, safety in relapsing MS
PHILADELPHIA – Higher doses of evobrutinib significantly improved that study endpoint, and were associated with numerical decreases in the annualized relapse rate versus placebo, according to a report presented at the annual meeting of the American Academy of Neurology.
Some grade 3-4 transaminase elevations were associated with evobrutinib, though these were asymptomatic, reversible, and occurred within the first 24 weeks of the 48-week treatment period, said investigator Xavier Montalban, MD, PhD, chairman and director of the department of neurology-neuroimmunology at Vall d’Hebron University Hospital in Barcelona.
“Overall, we do believe the results of the phase 2 study support further clinical development in relapsing multiple sclerosis,” Dr. Montalban said.
This study builds on previous observations that BTK plays an important role in immune functions related to the pathogenesis of MS, Dr. Montalban said. Evobrutinib in particular impacts B cells and myeloid cells along with pathways involved in MS-related inflammation, he added.
In the current randomized, phase 2, placebo-controlled study, 267 patients with relapsing MS were randomized to one of five arms: placebo, evobrutinib 25-mg daily, 75-mg daily, or 75-mg twice daily, or an open-label reference arm of dimethyl fumarate 240 mg twice daily.
Dr. Montalban presented the results of a 24-week treatment period plus a 24-week blinded extension period, during which placebo-treated patients crossed over to evobrutinib 25 mg daily, for a total of 48 weeks of treatment.
The primary study endpoint was the cumulative number of MRI-assessed T1 Gd+ lesions at weeks 12, 16, 20, and 24. Dr. Montalban said that evobrutinib in the two 75-mg arms significantly reduced enhancing lesions versus placebo over weeks 12-24, with lesion rate ratios of 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively. By contrast, the evobrutinib 25-mg arm did not significantly reduce the cumulative number of enhancing lesions versus placebo over that time period.
There was a rapid reduction in the mean number of enhancing lesions from baseline to the week-12 visit for those 75-mg dosing arms, which was sustained through subsequent visits, Dr. Montalban said.
There were no significant differences between arms in the annualized relapse rate at week 24, a key secondary endpoint of the study, according to the investigators. The annualized relapse rate was 0.37 for placebo, 0.57 for evobrutinib 25 mg daily, 0.13 for the 75-mg daily dose, 0.08 for the 75-mg twice-daily dose, and 0.20 for dimethyl fumarate. The magnitude of reduction was maintained at the 48-week evaluation for evobrutinib 75 mg twice daily, with an annualized relapse rate of 0.11, Dr. Montalban reported.
Most treatment-emergent adverse events were mild or moderate, according to the investigators.
Reported ALT elevations in the evobrutinib arms were mainly grade 1. While some grade 3-4 elevations were seen in the first 24 weeks of the study, they were reversible and did not have clinical consequences, according to Dr. Montalban.
Results of the study were published concurrently in the New England Journal of Medicine.
Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.
SOURCE: Montalban X et al. AAN 2019. Abstract S56.004.
PHILADELPHIA – Higher doses of evobrutinib significantly improved that study endpoint, and were associated with numerical decreases in the annualized relapse rate versus placebo, according to a report presented at the annual meeting of the American Academy of Neurology.
Some grade 3-4 transaminase elevations were associated with evobrutinib, though these were asymptomatic, reversible, and occurred within the first 24 weeks of the 48-week treatment period, said investigator Xavier Montalban, MD, PhD, chairman and director of the department of neurology-neuroimmunology at Vall d’Hebron University Hospital in Barcelona.
“Overall, we do believe the results of the phase 2 study support further clinical development in relapsing multiple sclerosis,” Dr. Montalban said.
This study builds on previous observations that BTK plays an important role in immune functions related to the pathogenesis of MS, Dr. Montalban said. Evobrutinib in particular impacts B cells and myeloid cells along with pathways involved in MS-related inflammation, he added.
In the current randomized, phase 2, placebo-controlled study, 267 patients with relapsing MS were randomized to one of five arms: placebo, evobrutinib 25-mg daily, 75-mg daily, or 75-mg twice daily, or an open-label reference arm of dimethyl fumarate 240 mg twice daily.
Dr. Montalban presented the results of a 24-week treatment period plus a 24-week blinded extension period, during which placebo-treated patients crossed over to evobrutinib 25 mg daily, for a total of 48 weeks of treatment.
The primary study endpoint was the cumulative number of MRI-assessed T1 Gd+ lesions at weeks 12, 16, 20, and 24. Dr. Montalban said that evobrutinib in the two 75-mg arms significantly reduced enhancing lesions versus placebo over weeks 12-24, with lesion rate ratios of 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively. By contrast, the evobrutinib 25-mg arm did not significantly reduce the cumulative number of enhancing lesions versus placebo over that time period.
There was a rapid reduction in the mean number of enhancing lesions from baseline to the week-12 visit for those 75-mg dosing arms, which was sustained through subsequent visits, Dr. Montalban said.
There were no significant differences between arms in the annualized relapse rate at week 24, a key secondary endpoint of the study, according to the investigators. The annualized relapse rate was 0.37 for placebo, 0.57 for evobrutinib 25 mg daily, 0.13 for the 75-mg daily dose, 0.08 for the 75-mg twice-daily dose, and 0.20 for dimethyl fumarate. The magnitude of reduction was maintained at the 48-week evaluation for evobrutinib 75 mg twice daily, with an annualized relapse rate of 0.11, Dr. Montalban reported.
Most treatment-emergent adverse events were mild or moderate, according to the investigators.
Reported ALT elevations in the evobrutinib arms were mainly grade 1. While some grade 3-4 elevations were seen in the first 24 weeks of the study, they were reversible and did not have clinical consequences, according to Dr. Montalban.
Results of the study were published concurrently in the New England Journal of Medicine.
Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.
SOURCE: Montalban X et al. AAN 2019. Abstract S56.004.
PHILADELPHIA – Higher doses of evobrutinib significantly improved that study endpoint, and were associated with numerical decreases in the annualized relapse rate versus placebo, according to a report presented at the annual meeting of the American Academy of Neurology.
Some grade 3-4 transaminase elevations were associated with evobrutinib, though these were asymptomatic, reversible, and occurred within the first 24 weeks of the 48-week treatment period, said investigator Xavier Montalban, MD, PhD, chairman and director of the department of neurology-neuroimmunology at Vall d’Hebron University Hospital in Barcelona.
“Overall, we do believe the results of the phase 2 study support further clinical development in relapsing multiple sclerosis,” Dr. Montalban said.
This study builds on previous observations that BTK plays an important role in immune functions related to the pathogenesis of MS, Dr. Montalban said. Evobrutinib in particular impacts B cells and myeloid cells along with pathways involved in MS-related inflammation, he added.
In the current randomized, phase 2, placebo-controlled study, 267 patients with relapsing MS were randomized to one of five arms: placebo, evobrutinib 25-mg daily, 75-mg daily, or 75-mg twice daily, or an open-label reference arm of dimethyl fumarate 240 mg twice daily.
Dr. Montalban presented the results of a 24-week treatment period plus a 24-week blinded extension period, during which placebo-treated patients crossed over to evobrutinib 25 mg daily, for a total of 48 weeks of treatment.
The primary study endpoint was the cumulative number of MRI-assessed T1 Gd+ lesions at weeks 12, 16, 20, and 24. Dr. Montalban said that evobrutinib in the two 75-mg arms significantly reduced enhancing lesions versus placebo over weeks 12-24, with lesion rate ratios of 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively. By contrast, the evobrutinib 25-mg arm did not significantly reduce the cumulative number of enhancing lesions versus placebo over that time period.
There was a rapid reduction in the mean number of enhancing lesions from baseline to the week-12 visit for those 75-mg dosing arms, which was sustained through subsequent visits, Dr. Montalban said.
There were no significant differences between arms in the annualized relapse rate at week 24, a key secondary endpoint of the study, according to the investigators. The annualized relapse rate was 0.37 for placebo, 0.57 for evobrutinib 25 mg daily, 0.13 for the 75-mg daily dose, 0.08 for the 75-mg twice-daily dose, and 0.20 for dimethyl fumarate. The magnitude of reduction was maintained at the 48-week evaluation for evobrutinib 75 mg twice daily, with an annualized relapse rate of 0.11, Dr. Montalban reported.
Most treatment-emergent adverse events were mild or moderate, according to the investigators.
Reported ALT elevations in the evobrutinib arms were mainly grade 1. While some grade 3-4 elevations were seen in the first 24 weeks of the study, they were reversible and did not have clinical consequences, according to Dr. Montalban.
Results of the study were published concurrently in the New England Journal of Medicine.
Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.
SOURCE: Montalban X et al. AAN 2019. Abstract S56.004.
FROM AAN 2019
Fingolimod reduced disease activity more than glatiramer acetate in RRMS: ASSESS study results
PHILADELPHIA – reported at the annual meeting of the American Academy of Neurology. The optimal efficacious dose of fingolimod was 0.5 mg once daily, according to the results of the ASSESS study, which also evaluated a 0.25-mg daily dose of fingolimod versus a 20-mg daily dose of glatiramer acetate.
Adverse events seen with fingolimod were consistent with the established safety profile of the immunomodulatory drug, according to investigator Bruce Cree, MD, PhD, of the UCSF Weill Institute for Neurosciences, department of neurology, University of California, San Francisco.
“I believe this is the first study to go head to head versus glatiramer acetate to show superiority,” Dr. Cree said in a podium presentation of the results.
While fingolimod 0.5 mg has shown superior efficacy over placebo and interferon beta-1a in previous phase 3 trials, head-to-head comparisons versus disease-modifying therapies can help inform treatment decisions in clinical practice, Dr. Cree and coinvestigators noted in the abstract that describes their results.
The randomized, three-armed, phase 3b ASSESS study included 12 months of dose-blinded treatment and 3 months of follow-up. Investigators enrolled 1,054 patients with relapsing-remitting MS, of whom about 74% were women and the average age was 40 years, Dr. Cree said in his presentation.
Annualized relapse rate, the primary endpoint of the study, was 0.153 for the fingolimod 0.5-mg arm, versus 0.258 for the glatiramer acetate 20-mg arm, for a 40.7% relative reduction (P = .013), Dr. Cree reported. By contrast, he said, the annualized relapse rate within the fingolimod 0.25-mg arm was 0.221, which was not statistically different versus glatiramer acetate.
The fingolimod 0.5-mg arm was also superior to glatiramer acetate on a number of radiographic endpoints at month 12, including new or newly enlarged T2 lesion count, change in T2 lesion volume, gadolinium-positive T1 lesion count, and gadolinium-positive T1 lesion volume, Dr. Cree said.
Adverse events and serious adverse events were “much as expected” in all three study groups, Dr. Cree said.
The observed safety with fingolimod was consistent with previously available data on fingolimod 0.5 mg, and the safety profile of the lower 0.25-mg dose seemed to be comparable with the 0.5-mg dose, according to his presentation.
Adverse events with fingolimod were “largely laboratory abnormalities,” that occurred more frequently in the fingolimod arms, he said. Although there was an apparent dose-dependent effect between the 0.25-mg and 0.5-mg doses, the overall proportion of patients experiencing low white blood cell counts or elevations in liver enzymes was low, he added.
Bradycardia was “infrequent” in both fingolimod groups in first-dose observations, though it did again occur with a dose-dependent effect, Dr. Cree said.
He reported bradycardia in two patients (0.5%) in the fingolimod 0.25-mg group and four (1.2%) in the fingolimod 0.5-mg group, while the number of patients requiring overnight hospitalizations was one (0.3%) and five (1.5%) in the 0.25- and 0.5-mg groups, respectively.
Hepatic enzyme abnormalities were the leading reason for discontinuation of fingolimod, while in contrast, drug hypersensitivity and injection site reactions led to discontinuations in the glatiramer acetate arm, he added.
Novartis sponsored the study. Dr. Cree provided disclosures related to Abbvie, Akili, Biogen, EMD Serono, GeNeuro and Novartis.
SOURCE: Cree B et al. AAN 2019, Abstract 56.009.
PHILADELPHIA – reported at the annual meeting of the American Academy of Neurology. The optimal efficacious dose of fingolimod was 0.5 mg once daily, according to the results of the ASSESS study, which also evaluated a 0.25-mg daily dose of fingolimod versus a 20-mg daily dose of glatiramer acetate.
Adverse events seen with fingolimod were consistent with the established safety profile of the immunomodulatory drug, according to investigator Bruce Cree, MD, PhD, of the UCSF Weill Institute for Neurosciences, department of neurology, University of California, San Francisco.
“I believe this is the first study to go head to head versus glatiramer acetate to show superiority,” Dr. Cree said in a podium presentation of the results.
While fingolimod 0.5 mg has shown superior efficacy over placebo and interferon beta-1a in previous phase 3 trials, head-to-head comparisons versus disease-modifying therapies can help inform treatment decisions in clinical practice, Dr. Cree and coinvestigators noted in the abstract that describes their results.
The randomized, three-armed, phase 3b ASSESS study included 12 months of dose-blinded treatment and 3 months of follow-up. Investigators enrolled 1,054 patients with relapsing-remitting MS, of whom about 74% were women and the average age was 40 years, Dr. Cree said in his presentation.
Annualized relapse rate, the primary endpoint of the study, was 0.153 for the fingolimod 0.5-mg arm, versus 0.258 for the glatiramer acetate 20-mg arm, for a 40.7% relative reduction (P = .013), Dr. Cree reported. By contrast, he said, the annualized relapse rate within the fingolimod 0.25-mg arm was 0.221, which was not statistically different versus glatiramer acetate.
The fingolimod 0.5-mg arm was also superior to glatiramer acetate on a number of radiographic endpoints at month 12, including new or newly enlarged T2 lesion count, change in T2 lesion volume, gadolinium-positive T1 lesion count, and gadolinium-positive T1 lesion volume, Dr. Cree said.
Adverse events and serious adverse events were “much as expected” in all three study groups, Dr. Cree said.
The observed safety with fingolimod was consistent with previously available data on fingolimod 0.5 mg, and the safety profile of the lower 0.25-mg dose seemed to be comparable with the 0.5-mg dose, according to his presentation.
Adverse events with fingolimod were “largely laboratory abnormalities,” that occurred more frequently in the fingolimod arms, he said. Although there was an apparent dose-dependent effect between the 0.25-mg and 0.5-mg doses, the overall proportion of patients experiencing low white blood cell counts or elevations in liver enzymes was low, he added.
Bradycardia was “infrequent” in both fingolimod groups in first-dose observations, though it did again occur with a dose-dependent effect, Dr. Cree said.
He reported bradycardia in two patients (0.5%) in the fingolimod 0.25-mg group and four (1.2%) in the fingolimod 0.5-mg group, while the number of patients requiring overnight hospitalizations was one (0.3%) and five (1.5%) in the 0.25- and 0.5-mg groups, respectively.
Hepatic enzyme abnormalities were the leading reason for discontinuation of fingolimod, while in contrast, drug hypersensitivity and injection site reactions led to discontinuations in the glatiramer acetate arm, he added.
Novartis sponsored the study. Dr. Cree provided disclosures related to Abbvie, Akili, Biogen, EMD Serono, GeNeuro and Novartis.
SOURCE: Cree B et al. AAN 2019, Abstract 56.009.
PHILADELPHIA – reported at the annual meeting of the American Academy of Neurology. The optimal efficacious dose of fingolimod was 0.5 mg once daily, according to the results of the ASSESS study, which also evaluated a 0.25-mg daily dose of fingolimod versus a 20-mg daily dose of glatiramer acetate.
Adverse events seen with fingolimod were consistent with the established safety profile of the immunomodulatory drug, according to investigator Bruce Cree, MD, PhD, of the UCSF Weill Institute for Neurosciences, department of neurology, University of California, San Francisco.
“I believe this is the first study to go head to head versus glatiramer acetate to show superiority,” Dr. Cree said in a podium presentation of the results.
While fingolimod 0.5 mg has shown superior efficacy over placebo and interferon beta-1a in previous phase 3 trials, head-to-head comparisons versus disease-modifying therapies can help inform treatment decisions in clinical practice, Dr. Cree and coinvestigators noted in the abstract that describes their results.
The randomized, three-armed, phase 3b ASSESS study included 12 months of dose-blinded treatment and 3 months of follow-up. Investigators enrolled 1,054 patients with relapsing-remitting MS, of whom about 74% were women and the average age was 40 years, Dr. Cree said in his presentation.
Annualized relapse rate, the primary endpoint of the study, was 0.153 for the fingolimod 0.5-mg arm, versus 0.258 for the glatiramer acetate 20-mg arm, for a 40.7% relative reduction (P = .013), Dr. Cree reported. By contrast, he said, the annualized relapse rate within the fingolimod 0.25-mg arm was 0.221, which was not statistically different versus glatiramer acetate.
The fingolimod 0.5-mg arm was also superior to glatiramer acetate on a number of radiographic endpoints at month 12, including new or newly enlarged T2 lesion count, change in T2 lesion volume, gadolinium-positive T1 lesion count, and gadolinium-positive T1 lesion volume, Dr. Cree said.
Adverse events and serious adverse events were “much as expected” in all three study groups, Dr. Cree said.
The observed safety with fingolimod was consistent with previously available data on fingolimod 0.5 mg, and the safety profile of the lower 0.25-mg dose seemed to be comparable with the 0.5-mg dose, according to his presentation.
Adverse events with fingolimod were “largely laboratory abnormalities,” that occurred more frequently in the fingolimod arms, he said. Although there was an apparent dose-dependent effect between the 0.25-mg and 0.5-mg doses, the overall proportion of patients experiencing low white blood cell counts or elevations in liver enzymes was low, he added.
Bradycardia was “infrequent” in both fingolimod groups in first-dose observations, though it did again occur with a dose-dependent effect, Dr. Cree said.
He reported bradycardia in two patients (0.5%) in the fingolimod 0.25-mg group and four (1.2%) in the fingolimod 0.5-mg group, while the number of patients requiring overnight hospitalizations was one (0.3%) and five (1.5%) in the 0.25- and 0.5-mg groups, respectively.
Hepatic enzyme abnormalities were the leading reason for discontinuation of fingolimod, while in contrast, drug hypersensitivity and injection site reactions led to discontinuations in the glatiramer acetate arm, he added.
Novartis sponsored the study. Dr. Cree provided disclosures related to Abbvie, Akili, Biogen, EMD Serono, GeNeuro and Novartis.
SOURCE: Cree B et al. AAN 2019, Abstract 56.009.
REPORTING FROM AAN 2019
Ocrelizumab effective, safe in relapsing-remitting MS patients
PHILADELPHIA – Ocrelizumab is effective and safe in patients with relapsing-remitting multiple sclerosis who had inadequate responses to previous disease-modifying treatments, said an investigator reporting interim results of a recent nonrandomized study.
The findings of the 600+ patient CHORDS study suggest a positive risk-to-benefit ratio over nearly 1 year for this anti-CD20 monoclonal antibody, said Thomas P. Leist, MD, of Thomas Jefferson University, Philadelphia, at the annual meeting of the American Academy of Neurology (AAN).
“MRI activity has been significantly attenuated in these individuals, particularly, in the period from 24 to 48 weeks, and the overall safety that has been observed to date has been in line with what has been observed in clinical trials with this medication,” Dr. Leist said in a podium presentation.
While previous investigations demonstrated superiority to treatment with interferon in patients with relapsing multiple sclerosis, this phase IIIb study was needed to further clarify the effects of the treatment following suboptimal response to several disease modifying treatments, according to Dr. Leist and his co-investigators.
The intention-to-treat population of CHORDS consisted of 608 patients who received disease-modifying therapy for 6 or more months and discontinued it due to suboptimal response, which was defined as one or more clinically reported relapses, one or more T1 gadolinium-enhancing lesions, or two or more enlarging T2 lesions. They all received a 600 mg dose of ocrelizumab every 24 weeks for as many as 96 weeks.
With 48 weeks of follow-up, the majority of patients had no relapses, no enhancing T1 lesions, no new or enlarging T2 lesions, and no confirmed progression of disability. In all, 54.5% of the patients experienced none of those events, according to Dr. Leist.
The adjusted annualized relapse rate in this cohort was 0.065, he reported.
New MRI activity included 48 new T1 gadolinium-enhancing lesions in 1,174 MRI scans, for an adjusted rate of 0.023, he also reported, while there were 679 new or enlarging T2 lesions on 1,175 scans, for an adjusted rate of 0.581.
The safety in this population was comparable to the overall safety profile of ocrelizumab seen in other studies, according to Dr. Leist. A total of 25 patients, or 4.1%, experienced a serious adverse event, though none led to treatment withdrawal and only one led to a dose modification or interruption, the data show.
Dr. Leist reported disclosures related to Alkermes, Bayer, Biogen, EMD Serono, Genentech, Inc., Novartis, Sanofi Genzyme, Sun Pharma, and Teva Neuroscience.
SOURCE: Leist TP, et al. Presented at the 2019 American Academy of Neurology (AAN) Annual Meeting, May 4-10, 2019. Philadelphia. Presentation S56.007.
PHILADELPHIA – Ocrelizumab is effective and safe in patients with relapsing-remitting multiple sclerosis who had inadequate responses to previous disease-modifying treatments, said an investigator reporting interim results of a recent nonrandomized study.
The findings of the 600+ patient CHORDS study suggest a positive risk-to-benefit ratio over nearly 1 year for this anti-CD20 monoclonal antibody, said Thomas P. Leist, MD, of Thomas Jefferson University, Philadelphia, at the annual meeting of the American Academy of Neurology (AAN).
“MRI activity has been significantly attenuated in these individuals, particularly, in the period from 24 to 48 weeks, and the overall safety that has been observed to date has been in line with what has been observed in clinical trials with this medication,” Dr. Leist said in a podium presentation.
While previous investigations demonstrated superiority to treatment with interferon in patients with relapsing multiple sclerosis, this phase IIIb study was needed to further clarify the effects of the treatment following suboptimal response to several disease modifying treatments, according to Dr. Leist and his co-investigators.
The intention-to-treat population of CHORDS consisted of 608 patients who received disease-modifying therapy for 6 or more months and discontinued it due to suboptimal response, which was defined as one or more clinically reported relapses, one or more T1 gadolinium-enhancing lesions, or two or more enlarging T2 lesions. They all received a 600 mg dose of ocrelizumab every 24 weeks for as many as 96 weeks.
With 48 weeks of follow-up, the majority of patients had no relapses, no enhancing T1 lesions, no new or enlarging T2 lesions, and no confirmed progression of disability. In all, 54.5% of the patients experienced none of those events, according to Dr. Leist.
The adjusted annualized relapse rate in this cohort was 0.065, he reported.
New MRI activity included 48 new T1 gadolinium-enhancing lesions in 1,174 MRI scans, for an adjusted rate of 0.023, he also reported, while there were 679 new or enlarging T2 lesions on 1,175 scans, for an adjusted rate of 0.581.
The safety in this population was comparable to the overall safety profile of ocrelizumab seen in other studies, according to Dr. Leist. A total of 25 patients, or 4.1%, experienced a serious adverse event, though none led to treatment withdrawal and only one led to a dose modification or interruption, the data show.
Dr. Leist reported disclosures related to Alkermes, Bayer, Biogen, EMD Serono, Genentech, Inc., Novartis, Sanofi Genzyme, Sun Pharma, and Teva Neuroscience.
SOURCE: Leist TP, et al. Presented at the 2019 American Academy of Neurology (AAN) Annual Meeting, May 4-10, 2019. Philadelphia. Presentation S56.007.
PHILADELPHIA – Ocrelizumab is effective and safe in patients with relapsing-remitting multiple sclerosis who had inadequate responses to previous disease-modifying treatments, said an investigator reporting interim results of a recent nonrandomized study.
The findings of the 600+ patient CHORDS study suggest a positive risk-to-benefit ratio over nearly 1 year for this anti-CD20 monoclonal antibody, said Thomas P. Leist, MD, of Thomas Jefferson University, Philadelphia, at the annual meeting of the American Academy of Neurology (AAN).
“MRI activity has been significantly attenuated in these individuals, particularly, in the period from 24 to 48 weeks, and the overall safety that has been observed to date has been in line with what has been observed in clinical trials with this medication,” Dr. Leist said in a podium presentation.
While previous investigations demonstrated superiority to treatment with interferon in patients with relapsing multiple sclerosis, this phase IIIb study was needed to further clarify the effects of the treatment following suboptimal response to several disease modifying treatments, according to Dr. Leist and his co-investigators.
The intention-to-treat population of CHORDS consisted of 608 patients who received disease-modifying therapy for 6 or more months and discontinued it due to suboptimal response, which was defined as one or more clinically reported relapses, one or more T1 gadolinium-enhancing lesions, or two or more enlarging T2 lesions. They all received a 600 mg dose of ocrelizumab every 24 weeks for as many as 96 weeks.
With 48 weeks of follow-up, the majority of patients had no relapses, no enhancing T1 lesions, no new or enlarging T2 lesions, and no confirmed progression of disability. In all, 54.5% of the patients experienced none of those events, according to Dr. Leist.
The adjusted annualized relapse rate in this cohort was 0.065, he reported.
New MRI activity included 48 new T1 gadolinium-enhancing lesions in 1,174 MRI scans, for an adjusted rate of 0.023, he also reported, while there were 679 new or enlarging T2 lesions on 1,175 scans, for an adjusted rate of 0.581.
The safety in this population was comparable to the overall safety profile of ocrelizumab seen in other studies, according to Dr. Leist. A total of 25 patients, or 4.1%, experienced a serious adverse event, though none led to treatment withdrawal and only one led to a dose modification or interruption, the data show.
Dr. Leist reported disclosures related to Alkermes, Bayer, Biogen, EMD Serono, Genentech, Inc., Novartis, Sanofi Genzyme, Sun Pharma, and Teva Neuroscience.
SOURCE: Leist TP, et al. Presented at the 2019 American Academy of Neurology (AAN) Annual Meeting, May 4-10, 2019. Philadelphia. Presentation S56.007.
FROM AAN 2019
Deutetrabenazine benefit may increase over time in patients with tardive dyskinesia
PHILADELPHIA –
The mean Abnormal Involuntary Movement Scale (AIMS) score in the study continued to increase over 3 years of treatment with this VMAT2 inhibitor, which was safe and well tolerated over the course of the study, said investigator Robert A. Hauser, MD, MBA, director of the Parkinson’s and Movement Disorder Center and professor in the department of neurology at the University of South Florida in Tampa.
The apparent improvement over time was “fascinating” to observe, Dr. Hauser said. The finding deserves further study to identify potential confounders, such as rater bias over time or placebo effects, and if those “trivial” causes can be ruled out to determine a potential mechanism of action.
“I will also say that the mechanism may not be that important if we can really show this important clinical effect,” he said. “So I think this needs more work.”
The FDA approved deutetrabenazine (Austedo, Teva) for tardive dyskinesia treatment based on ARM-TD and AIM-TD, two randomized, double-blind, placebo-controlled trials. Those studies demonstrated improvements in AIMS scores for the VMAT2 inhibitor versus placebo, with low rates of adverse events and discontinuations, Dr. Hauser said.
Dr. Hauser presented results up to week 145 from C-20, an ongoing, 3-year, open-label extension study designed to evaluate the agent’s long-term safety and efficacy.
A total of 343 patients from ARM-TD and AIM-TD rolled over directly into C-20, started at 12 mg/day of deutetrabenazine, and titrated until adequate tardive dyskinesia control was achieved, up to 48 mg/day. Sixty percent of the patients had psychotic disorders as the background comorbid illness, while 40% had mood disorders, according to the interim report.
The mean AIMS score was 10.9 at baseline, 6.0 at 54 weeks, 5.8 at 106 weeks, and 4.1 at 145 weeks, the report showed. The corresponding change in AIMS score decreased from baseline for patients who remained in the study, from –4.8 at 54 weeks to –5.6 at 106 weeks and –7.0 at 145 weeks.*
A subsequent completer analysis showed that the apparent improvement in efficacy over the long term was not due to poor responders dropping out over time, Dr. Hauser said.
“I think the data clearly show the benefit is maintained, and intriguingly, I think they suggest that there may be increasing benefit over time,” he added.
The treatment was safe and well tolerated in long-term use. The most common adverse events were anxiety, somnolence, fatigue, insomnia, and headache. Adverse events did not increase in frequency from the parent studies to the open-label study, he noted.
The study was sponsored by Teva Pharmaceuticals. Dr. Hauser reported disclosures related to Teva, AbbVie, AstraZeneca, Biotie Thrapies, Cynapsus Therapeutics, Neurocrine Biosciences, Sunovion Pharmaceuticals, and Pfizer, among others.
SOURCE: Hauser RA et al. AAN 2019. Abstract S4.009.
*Correction, 6/26/19 An earlier version of this article mischaracterized changes in the mean Abnormal Involuntary Movement Scale scores during treatment.
PHILADELPHIA –
The mean Abnormal Involuntary Movement Scale (AIMS) score in the study continued to increase over 3 years of treatment with this VMAT2 inhibitor, which was safe and well tolerated over the course of the study, said investigator Robert A. Hauser, MD, MBA, director of the Parkinson’s and Movement Disorder Center and professor in the department of neurology at the University of South Florida in Tampa.
The apparent improvement over time was “fascinating” to observe, Dr. Hauser said. The finding deserves further study to identify potential confounders, such as rater bias over time or placebo effects, and if those “trivial” causes can be ruled out to determine a potential mechanism of action.
“I will also say that the mechanism may not be that important if we can really show this important clinical effect,” he said. “So I think this needs more work.”
The FDA approved deutetrabenazine (Austedo, Teva) for tardive dyskinesia treatment based on ARM-TD and AIM-TD, two randomized, double-blind, placebo-controlled trials. Those studies demonstrated improvements in AIMS scores for the VMAT2 inhibitor versus placebo, with low rates of adverse events and discontinuations, Dr. Hauser said.
Dr. Hauser presented results up to week 145 from C-20, an ongoing, 3-year, open-label extension study designed to evaluate the agent’s long-term safety and efficacy.
A total of 343 patients from ARM-TD and AIM-TD rolled over directly into C-20, started at 12 mg/day of deutetrabenazine, and titrated until adequate tardive dyskinesia control was achieved, up to 48 mg/day. Sixty percent of the patients had psychotic disorders as the background comorbid illness, while 40% had mood disorders, according to the interim report.
The mean AIMS score was 10.9 at baseline, 6.0 at 54 weeks, 5.8 at 106 weeks, and 4.1 at 145 weeks, the report showed. The corresponding change in AIMS score decreased from baseline for patients who remained in the study, from –4.8 at 54 weeks to –5.6 at 106 weeks and –7.0 at 145 weeks.*
A subsequent completer analysis showed that the apparent improvement in efficacy over the long term was not due to poor responders dropping out over time, Dr. Hauser said.
“I think the data clearly show the benefit is maintained, and intriguingly, I think they suggest that there may be increasing benefit over time,” he added.
The treatment was safe and well tolerated in long-term use. The most common adverse events were anxiety, somnolence, fatigue, insomnia, and headache. Adverse events did not increase in frequency from the parent studies to the open-label study, he noted.
The study was sponsored by Teva Pharmaceuticals. Dr. Hauser reported disclosures related to Teva, AbbVie, AstraZeneca, Biotie Thrapies, Cynapsus Therapeutics, Neurocrine Biosciences, Sunovion Pharmaceuticals, and Pfizer, among others.
SOURCE: Hauser RA et al. AAN 2019. Abstract S4.009.
*Correction, 6/26/19 An earlier version of this article mischaracterized changes in the mean Abnormal Involuntary Movement Scale scores during treatment.
PHILADELPHIA –
The mean Abnormal Involuntary Movement Scale (AIMS) score in the study continued to increase over 3 years of treatment with this VMAT2 inhibitor, which was safe and well tolerated over the course of the study, said investigator Robert A. Hauser, MD, MBA, director of the Parkinson’s and Movement Disorder Center and professor in the department of neurology at the University of South Florida in Tampa.
The apparent improvement over time was “fascinating” to observe, Dr. Hauser said. The finding deserves further study to identify potential confounders, such as rater bias over time or placebo effects, and if those “trivial” causes can be ruled out to determine a potential mechanism of action.
“I will also say that the mechanism may not be that important if we can really show this important clinical effect,” he said. “So I think this needs more work.”
The FDA approved deutetrabenazine (Austedo, Teva) for tardive dyskinesia treatment based on ARM-TD and AIM-TD, two randomized, double-blind, placebo-controlled trials. Those studies demonstrated improvements in AIMS scores for the VMAT2 inhibitor versus placebo, with low rates of adverse events and discontinuations, Dr. Hauser said.
Dr. Hauser presented results up to week 145 from C-20, an ongoing, 3-year, open-label extension study designed to evaluate the agent’s long-term safety and efficacy.
A total of 343 patients from ARM-TD and AIM-TD rolled over directly into C-20, started at 12 mg/day of deutetrabenazine, and titrated until adequate tardive dyskinesia control was achieved, up to 48 mg/day. Sixty percent of the patients had psychotic disorders as the background comorbid illness, while 40% had mood disorders, according to the interim report.
The mean AIMS score was 10.9 at baseline, 6.0 at 54 weeks, 5.8 at 106 weeks, and 4.1 at 145 weeks, the report showed. The corresponding change in AIMS score decreased from baseline for patients who remained in the study, from –4.8 at 54 weeks to –5.6 at 106 weeks and –7.0 at 145 weeks.*
A subsequent completer analysis showed that the apparent improvement in efficacy over the long term was not due to poor responders dropping out over time, Dr. Hauser said.
“I think the data clearly show the benefit is maintained, and intriguingly, I think they suggest that there may be increasing benefit over time,” he added.
The treatment was safe and well tolerated in long-term use. The most common adverse events were anxiety, somnolence, fatigue, insomnia, and headache. Adverse events did not increase in frequency from the parent studies to the open-label study, he noted.
The study was sponsored by Teva Pharmaceuticals. Dr. Hauser reported disclosures related to Teva, AbbVie, AstraZeneca, Biotie Thrapies, Cynapsus Therapeutics, Neurocrine Biosciences, Sunovion Pharmaceuticals, and Pfizer, among others.
SOURCE: Hauser RA et al. AAN 2019. Abstract S4.009.
*Correction, 6/26/19 An earlier version of this article mischaracterized changes in the mean Abnormal Involuntary Movement Scale scores during treatment.
REPORTING FROM AAN 2019
Key clinical point: The benefit of deutetrabenazine in patients with tardive dyskinesia is maintained in the long term and may actually increase over time, though further study is needed.
Major finding: Change from baseline in Abnormal Involuntary Movement Scale (AIMS) score decreased from –4.8 at 54 weeks to –5.6 at 106 weeks and –7.0 at 154 weeks.
Study details: Interim analysis of C-20, an open-label extension study including 343 patients initially enrolled in one of two pivotal randomized phase 3 studies.
Disclosures: The study was sponsored by Teva Pharmaceuticals. Dr. Hauser reported disclosures related to Teva, AbbVie, AstraZeneca, Biotie Thrapies, Cynapsus Therapeutics, Neurocrine Biosciences, Sunovion Pharmaceuticals, and Pfizer, among others.
Source: Hauser RA et al. AAN 2019. Abstract S4.009.