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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Long-term specialist care reduces post-RYGB anemia risk
Patients who underwent Roux-en-Y gastric bypass surgery (RYGB) without long-term bariatric specialist follow-up experienced a significantly higher rate of anemia at 10 years than did patients who had such specialist follow-up, according to findings from a database review.
Among 74 patients available for analysis – 58 men and 16 women with a mean age of 51 years who underwent RYGB at a single Veterans Affairs medical center between 2002 and 2006 – the mean rate of preoperative anemia was 20% (15 patients). The rate increased to 28% (21 patients) at 1 year, 31% (23 patients) at 5 years, and 47% (35 patients) at 10 years, according to a research letter by Gao Linda Chen, MD, and her colleagues in the surgical service of the VA Palo Alto (Calif.) Health Care System (JAMA Surg. 2017. Sep 20. doi: 10.1001/jamasurg.2017.3158).
Among 58 patients with no bariatric specialist follow-up after 5 years, the anemia rate increased from 22% (13 patients) before surgery to 57% (33 patients) at 10 years, while the corresponding rates for those with specialty follow-up were 19% (3 patients) and 13% (2 patients). After adjustment for preoperative anemia, those without specialist follow-up had significantly higher odds of anemia at 10 years (odds ratio, 6.1).
“Long-term complications of RYGB, such as anemia, may go unrecognized by nonbariatric specialists,” the investigators wrote, noting that the high rates of anemia at 10 years “may reflect a mixed vitamin and mineral deficiency, because patients had normocytic anemia.
“Our study suggests that follow-up with bariatric specialists more than 5 years after surgery, rather than with specialists with no bariatric expertise, can decrease long-term anemia risk,” they continued. “This finding may demonstrate the bariatric specialist’s specific understanding of the long-term risk for nutritional deficiency after RYGB and the importance of vitamin and mineral supplementation.”
The findings suggest a bariatric team approach with planning for long-term follow-up. “We implemented a hub-and-spoke model for bariatric care, including health care specialist education, in which the bariatric team communicates regularly with the patient’s primary care clinician before and after surgery.”
Although the study is limited by small sample size, the findings nevertheless underscore that “long-term follow-up should be an integral part of bariatric programs, and additional studies are needed to identify potential barriers to successful follow-up,” they concluded.
The authors reported having no disclosures.
Patients who underwent Roux-en-Y gastric bypass surgery (RYGB) without long-term bariatric specialist follow-up experienced a significantly higher rate of anemia at 10 years than did patients who had such specialist follow-up, according to findings from a database review.
Among 74 patients available for analysis – 58 men and 16 women with a mean age of 51 years who underwent RYGB at a single Veterans Affairs medical center between 2002 and 2006 – the mean rate of preoperative anemia was 20% (15 patients). The rate increased to 28% (21 patients) at 1 year, 31% (23 patients) at 5 years, and 47% (35 patients) at 10 years, according to a research letter by Gao Linda Chen, MD, and her colleagues in the surgical service of the VA Palo Alto (Calif.) Health Care System (JAMA Surg. 2017. Sep 20. doi: 10.1001/jamasurg.2017.3158).
Among 58 patients with no bariatric specialist follow-up after 5 years, the anemia rate increased from 22% (13 patients) before surgery to 57% (33 patients) at 10 years, while the corresponding rates for those with specialty follow-up were 19% (3 patients) and 13% (2 patients). After adjustment for preoperative anemia, those without specialist follow-up had significantly higher odds of anemia at 10 years (odds ratio, 6.1).
“Long-term complications of RYGB, such as anemia, may go unrecognized by nonbariatric specialists,” the investigators wrote, noting that the high rates of anemia at 10 years “may reflect a mixed vitamin and mineral deficiency, because patients had normocytic anemia.
“Our study suggests that follow-up with bariatric specialists more than 5 years after surgery, rather than with specialists with no bariatric expertise, can decrease long-term anemia risk,” they continued. “This finding may demonstrate the bariatric specialist’s specific understanding of the long-term risk for nutritional deficiency after RYGB and the importance of vitamin and mineral supplementation.”
The findings suggest a bariatric team approach with planning for long-term follow-up. “We implemented a hub-and-spoke model for bariatric care, including health care specialist education, in which the bariatric team communicates regularly with the patient’s primary care clinician before and after surgery.”
Although the study is limited by small sample size, the findings nevertheless underscore that “long-term follow-up should be an integral part of bariatric programs, and additional studies are needed to identify potential barriers to successful follow-up,” they concluded.
The authors reported having no disclosures.
Patients who underwent Roux-en-Y gastric bypass surgery (RYGB) without long-term bariatric specialist follow-up experienced a significantly higher rate of anemia at 10 years than did patients who had such specialist follow-up, according to findings from a database review.
Among 74 patients available for analysis – 58 men and 16 women with a mean age of 51 years who underwent RYGB at a single Veterans Affairs medical center between 2002 and 2006 – the mean rate of preoperative anemia was 20% (15 patients). The rate increased to 28% (21 patients) at 1 year, 31% (23 patients) at 5 years, and 47% (35 patients) at 10 years, according to a research letter by Gao Linda Chen, MD, and her colleagues in the surgical service of the VA Palo Alto (Calif.) Health Care System (JAMA Surg. 2017. Sep 20. doi: 10.1001/jamasurg.2017.3158).
Among 58 patients with no bariatric specialist follow-up after 5 years, the anemia rate increased from 22% (13 patients) before surgery to 57% (33 patients) at 10 years, while the corresponding rates for those with specialty follow-up were 19% (3 patients) and 13% (2 patients). After adjustment for preoperative anemia, those without specialist follow-up had significantly higher odds of anemia at 10 years (odds ratio, 6.1).
“Long-term complications of RYGB, such as anemia, may go unrecognized by nonbariatric specialists,” the investigators wrote, noting that the high rates of anemia at 10 years “may reflect a mixed vitamin and mineral deficiency, because patients had normocytic anemia.
“Our study suggests that follow-up with bariatric specialists more than 5 years after surgery, rather than with specialists with no bariatric expertise, can decrease long-term anemia risk,” they continued. “This finding may demonstrate the bariatric specialist’s specific understanding of the long-term risk for nutritional deficiency after RYGB and the importance of vitamin and mineral supplementation.”
The findings suggest a bariatric team approach with planning for long-term follow-up. “We implemented a hub-and-spoke model for bariatric care, including health care specialist education, in which the bariatric team communicates regularly with the patient’s primary care clinician before and after surgery.”
Although the study is limited by small sample size, the findings nevertheless underscore that “long-term follow-up should be an integral part of bariatric programs, and additional studies are needed to identify potential barriers to successful follow-up,” they concluded.
The authors reported having no disclosures.
FROM JAMA SURGERY
Key clinical point:
Major finding: RYGB patients without specialist follow-up had significantly higher odds of anemia at 10 years (adjusted odds ratio, 6.1).
Data source: A retrospective review of 74 patients from a prospective 10-year database.
Disclosures: The authors reported having no disclosures.
LUME-Mesa trial: Nintedanib improves PFS in mesothelioma
CHICAGO – Adding the oral kinase inhibitor nintedanib to pemetrexed/cisplatin resulted in substantial improvements in outcomes in patients with unresectable malignant pleural mesothelioma in phase 2 of the randomized, placebo-controlled phase 2/3 LUME-Meso study.
The effects were particularly pronounced among those with epithelioid histology, Jose Barrueco, PhD, of Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
Progression-free survival – the primary endpoint of the study – was improved in 44 patients randomized to receive up to six cycles of pemetrexed/cisplatin plus nintedanib, compared with 43 patients who received pemetrexed/cisplatin plus placebo (median 9.4 vs. 5.7 months; hazard ratio, 0.54), Dr. Barrueco said.
In the 89% of patients with epithelioid malignant pleural mesothelioma, progression-free survival was a median of 9.7 vs. 5.7 months with nintedanib vs. placebo (HR, 0.49).
There was a trend toward improved overall survival in the nintedanib group vs. the placebo group, (median 18.3 vs. 14.2 months; HR, 0.77; P = .319), and overall survival was slightly better in those with epithelioid histology (median 20.6 vs. 15.2 months ; HR, 0.70; P = .197).
Consistent with these results, the adjusted mean change in forced vital capacity at cycle eight also favored nintedanib over placebo (+10.0 vs. +2.8 for a mean treatment difference of 7.2 overall, and +14.1 vs. +4.2 for a mean treatment difference of 9.9 in those with epithelioid histology).
“Overall frequency of adverse events was consistent with the known safety profile of nintedanib,” Dr. Barrueco said, noting that most adverse events were reversible with dose reduction.
Study participants were chemotherapy-naive patients with a mean age of 67 years and Eastern Cooperative Oncology Group performance status of 0-1. They received pemetrexed at a dose of 500 mg/m2 and cisplatin at a dose of 75 mg/m2 on day 1 plus either nintedanib at a dose of 200 mg twice daily on days 2-21 or placebo, followed by monotherapy with nintedanib or placebo until progression or unacceptable toxicity.
“In conclusion, nintedanib plus pemetrexed/cisplatin demonstrated a signal for clinical benefit in the first-time treatment of patients with malignant pleural mesothelioma. This was evident in all endpoints of the trial, and consistently showed benefit for the nintedanib group,” Mr. Barrueco said, noting that phase 3 of the LUME-Meso study is now recruiting.
CHICAGO – Adding the oral kinase inhibitor nintedanib to pemetrexed/cisplatin resulted in substantial improvements in outcomes in patients with unresectable malignant pleural mesothelioma in phase 2 of the randomized, placebo-controlled phase 2/3 LUME-Meso study.
The effects were particularly pronounced among those with epithelioid histology, Jose Barrueco, PhD, of Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
Progression-free survival – the primary endpoint of the study – was improved in 44 patients randomized to receive up to six cycles of pemetrexed/cisplatin plus nintedanib, compared with 43 patients who received pemetrexed/cisplatin plus placebo (median 9.4 vs. 5.7 months; hazard ratio, 0.54), Dr. Barrueco said.
In the 89% of patients with epithelioid malignant pleural mesothelioma, progression-free survival was a median of 9.7 vs. 5.7 months with nintedanib vs. placebo (HR, 0.49).
There was a trend toward improved overall survival in the nintedanib group vs. the placebo group, (median 18.3 vs. 14.2 months; HR, 0.77; P = .319), and overall survival was slightly better in those with epithelioid histology (median 20.6 vs. 15.2 months ; HR, 0.70; P = .197).
Consistent with these results, the adjusted mean change in forced vital capacity at cycle eight also favored nintedanib over placebo (+10.0 vs. +2.8 for a mean treatment difference of 7.2 overall, and +14.1 vs. +4.2 for a mean treatment difference of 9.9 in those with epithelioid histology).
“Overall frequency of adverse events was consistent with the known safety profile of nintedanib,” Dr. Barrueco said, noting that most adverse events were reversible with dose reduction.
Study participants were chemotherapy-naive patients with a mean age of 67 years and Eastern Cooperative Oncology Group performance status of 0-1. They received pemetrexed at a dose of 500 mg/m2 and cisplatin at a dose of 75 mg/m2 on day 1 plus either nintedanib at a dose of 200 mg twice daily on days 2-21 or placebo, followed by monotherapy with nintedanib or placebo until progression or unacceptable toxicity.
“In conclusion, nintedanib plus pemetrexed/cisplatin demonstrated a signal for clinical benefit in the first-time treatment of patients with malignant pleural mesothelioma. This was evident in all endpoints of the trial, and consistently showed benefit for the nintedanib group,” Mr. Barrueco said, noting that phase 3 of the LUME-Meso study is now recruiting.
CHICAGO – Adding the oral kinase inhibitor nintedanib to pemetrexed/cisplatin resulted in substantial improvements in outcomes in patients with unresectable malignant pleural mesothelioma in phase 2 of the randomized, placebo-controlled phase 2/3 LUME-Meso study.
The effects were particularly pronounced among those with epithelioid histology, Jose Barrueco, PhD, of Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
Progression-free survival – the primary endpoint of the study – was improved in 44 patients randomized to receive up to six cycles of pemetrexed/cisplatin plus nintedanib, compared with 43 patients who received pemetrexed/cisplatin plus placebo (median 9.4 vs. 5.7 months; hazard ratio, 0.54), Dr. Barrueco said.
In the 89% of patients with epithelioid malignant pleural mesothelioma, progression-free survival was a median of 9.7 vs. 5.7 months with nintedanib vs. placebo (HR, 0.49).
There was a trend toward improved overall survival in the nintedanib group vs. the placebo group, (median 18.3 vs. 14.2 months; HR, 0.77; P = .319), and overall survival was slightly better in those with epithelioid histology (median 20.6 vs. 15.2 months ; HR, 0.70; P = .197).
Consistent with these results, the adjusted mean change in forced vital capacity at cycle eight also favored nintedanib over placebo (+10.0 vs. +2.8 for a mean treatment difference of 7.2 overall, and +14.1 vs. +4.2 for a mean treatment difference of 9.9 in those with epithelioid histology).
“Overall frequency of adverse events was consistent with the known safety profile of nintedanib,” Dr. Barrueco said, noting that most adverse events were reversible with dose reduction.
Study participants were chemotherapy-naive patients with a mean age of 67 years and Eastern Cooperative Oncology Group performance status of 0-1. They received pemetrexed at a dose of 500 mg/m2 and cisplatin at a dose of 75 mg/m2 on day 1 plus either nintedanib at a dose of 200 mg twice daily on days 2-21 or placebo, followed by monotherapy with nintedanib or placebo until progression or unacceptable toxicity.
“In conclusion, nintedanib plus pemetrexed/cisplatin demonstrated a signal for clinical benefit in the first-time treatment of patients with malignant pleural mesothelioma. This was evident in all endpoints of the trial, and consistently showed benefit for the nintedanib group,” Mr. Barrueco said, noting that phase 3 of the LUME-Meso study is now recruiting.
AT A SYMPOSIUM IN THORACIC ONCOLOGY
Key clinical point:
Major finding: Overall median PFS with nintedanib vs. placebo was 9.4 vs. 5.7 months (HR, 0.54).
Data source: Phase 2 of the LUME-Meso trial with 87 patients.
Disclosures: Dr. Barrueco is an employee of Boehringer Ingelheim.
Leukocyte activation test–based elimination diet improves IBS symptoms
Elimination diets guided by leukocyte activation tests reduced symptoms in patients with irritable bowel syndrome (IBS) in a parallel-group, double-blind, randomized controlled trial.
Study participants were randomized to a 4-week diet with individualized guidance to either eliminate foods with positive assay results and to allow foods with negative assay results (intervention group), or to eliminate foods with negative assay results and allow foods with positive assay results (comparison group). The 29 patients in the intervention group had significantly greater increases in mean IBS Global Improvement Scale scores at 4 weeks and 8 weeks vs. the 29 patients in the comparison group (mean between-group differences, 0.86 and 1.22 points, respectively), reported Ather Ali, ND, of Yale University, New Haven, Conn., and colleagues (BMJ Open Gastro. 2017;0:e000164. doi: 10.1136/bmjgast-2017-000164).
Improvements were seen in IBS Adequate Relief and Quality of Life scores in the intervention group, but the differences between the groups were not statistically significant. No adverse effects related to the intervention were reported, they said.
Of note, strong responders in the intervention group experienced significant reductions in neutrophil elastase.
IBS is a prevalent, costly, and often disabling condition, but assessing food intolerance in clinical practice is challenging, the investigators said, adding that while a number of commercially available blood tests claim to diagnose food intolerance – including leukocyte activation tests, which are among the most widely used for this purpose – no rigorous studies of the tests have been published.
For the current study, adults aged 18-75 years who met Rome III criteria for any subtype of IBS and had active symptoms were enrolled from an academic health center in Connecticut. The leukocyte activation test was used to culture peripheral blood leukocytes with standardized individual food extracts, producing either a positive or negative result, which then guided the food elimination.
The findings demonstrate that “a diet guided by leukocyte activation testing results in demonstrable clinical improvement in IBS,” they wrote, noting that dietary changes based on a leukocyte activation test may be less restrictive than those associated with a low–fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (low FODMAPs) diet (which has also shown promise as “an efficacious, although burdensome, dietary intervention for IBS”), and may result in better long-term adherence.
“These clinical results, associated with a reduction in plasma neutrophil elastase, have implication for better understanding the role of food intolerance and the pathophysiology of IBS,” they said, adding that “future studies, ideally multisite and in larger samples, can assess comparative effects of other dietary interventions in IBS, the effects of restricting specific foods, and whether dietary changes guided by leukocyte activation testing affect other conditions.”
Cell Science Systems funded the study. The authors reported having no disclosures.
Elimination diets guided by leukocyte activation tests reduced symptoms in patients with irritable bowel syndrome (IBS) in a parallel-group, double-blind, randomized controlled trial.
Study participants were randomized to a 4-week diet with individualized guidance to either eliminate foods with positive assay results and to allow foods with negative assay results (intervention group), or to eliminate foods with negative assay results and allow foods with positive assay results (comparison group). The 29 patients in the intervention group had significantly greater increases in mean IBS Global Improvement Scale scores at 4 weeks and 8 weeks vs. the 29 patients in the comparison group (mean between-group differences, 0.86 and 1.22 points, respectively), reported Ather Ali, ND, of Yale University, New Haven, Conn., and colleagues (BMJ Open Gastro. 2017;0:e000164. doi: 10.1136/bmjgast-2017-000164).
Improvements were seen in IBS Adequate Relief and Quality of Life scores in the intervention group, but the differences between the groups were not statistically significant. No adverse effects related to the intervention were reported, they said.
Of note, strong responders in the intervention group experienced significant reductions in neutrophil elastase.
IBS is a prevalent, costly, and often disabling condition, but assessing food intolerance in clinical practice is challenging, the investigators said, adding that while a number of commercially available blood tests claim to diagnose food intolerance – including leukocyte activation tests, which are among the most widely used for this purpose – no rigorous studies of the tests have been published.
For the current study, adults aged 18-75 years who met Rome III criteria for any subtype of IBS and had active symptoms were enrolled from an academic health center in Connecticut. The leukocyte activation test was used to culture peripheral blood leukocytes with standardized individual food extracts, producing either a positive or negative result, which then guided the food elimination.
The findings demonstrate that “a diet guided by leukocyte activation testing results in demonstrable clinical improvement in IBS,” they wrote, noting that dietary changes based on a leukocyte activation test may be less restrictive than those associated with a low–fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (low FODMAPs) diet (which has also shown promise as “an efficacious, although burdensome, dietary intervention for IBS”), and may result in better long-term adherence.
“These clinical results, associated with a reduction in plasma neutrophil elastase, have implication for better understanding the role of food intolerance and the pathophysiology of IBS,” they said, adding that “future studies, ideally multisite and in larger samples, can assess comparative effects of other dietary interventions in IBS, the effects of restricting specific foods, and whether dietary changes guided by leukocyte activation testing affect other conditions.”
Cell Science Systems funded the study. The authors reported having no disclosures.
Elimination diets guided by leukocyte activation tests reduced symptoms in patients with irritable bowel syndrome (IBS) in a parallel-group, double-blind, randomized controlled trial.
Study participants were randomized to a 4-week diet with individualized guidance to either eliminate foods with positive assay results and to allow foods with negative assay results (intervention group), or to eliminate foods with negative assay results and allow foods with positive assay results (comparison group). The 29 patients in the intervention group had significantly greater increases in mean IBS Global Improvement Scale scores at 4 weeks and 8 weeks vs. the 29 patients in the comparison group (mean between-group differences, 0.86 and 1.22 points, respectively), reported Ather Ali, ND, of Yale University, New Haven, Conn., and colleagues (BMJ Open Gastro. 2017;0:e000164. doi: 10.1136/bmjgast-2017-000164).
Improvements were seen in IBS Adequate Relief and Quality of Life scores in the intervention group, but the differences between the groups were not statistically significant. No adverse effects related to the intervention were reported, they said.
Of note, strong responders in the intervention group experienced significant reductions in neutrophil elastase.
IBS is a prevalent, costly, and often disabling condition, but assessing food intolerance in clinical practice is challenging, the investigators said, adding that while a number of commercially available blood tests claim to diagnose food intolerance – including leukocyte activation tests, which are among the most widely used for this purpose – no rigorous studies of the tests have been published.
For the current study, adults aged 18-75 years who met Rome III criteria for any subtype of IBS and had active symptoms were enrolled from an academic health center in Connecticut. The leukocyte activation test was used to culture peripheral blood leukocytes with standardized individual food extracts, producing either a positive or negative result, which then guided the food elimination.
The findings demonstrate that “a diet guided by leukocyte activation testing results in demonstrable clinical improvement in IBS,” they wrote, noting that dietary changes based on a leukocyte activation test may be less restrictive than those associated with a low–fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (low FODMAPs) diet (which has also shown promise as “an efficacious, although burdensome, dietary intervention for IBS”), and may result in better long-term adherence.
“These clinical results, associated with a reduction in plasma neutrophil elastase, have implication for better understanding the role of food intolerance and the pathophysiology of IBS,” they said, adding that “future studies, ideally multisite and in larger samples, can assess comparative effects of other dietary interventions in IBS, the effects of restricting specific foods, and whether dietary changes guided by leukocyte activation testing affect other conditions.”
Cell Science Systems funded the study. The authors reported having no disclosures.
FROM BMJ OPEN GASTROENTEROLOGY
Key clinical point:
Major finding: Mean IBS Global Improvement Scale scores improved significantly more in the intervention vs. comparison group at 4 weeks and 8 weeks (mean between-group differences of 0.86 and 1.22 points, respectively).
Data source: A parallel-group, double-blind, randomized controlled trial of 58 IBS patients.
Disclosures: Cell Science Systems funded the study. The authors reported having no disclosures.
Retrospective review: No difference in PFS, OS with radiation before PD-1/PD-L1 inhibition
CHICAGO – Exposure to radiation therapy prior to PD-1/PD-L1 therapy was not associated with improved outcomes in a retrospective review of 66 lung cancer patients.
The patients had stage IIIB or IV non–small cell lung cancer, median age of 64 years, received at least 6 weeks of single-agent anti-PD-1/PD-L1 therapy in the second-line setting or beyond, and had survived at least 8 weeks from immunotherapy initiation. Compared with 13 patients who received no radiation therapy, the 53 who received any prior radiation therapy – including 44 with extracranial radiation and 22 with intracranial radiation – did not differ significantly with respect to progression-free survival (median 4-5 months; hazard ratio, 0.83), or overall survival (median of about 12 months in both groups; HR, 0.96), Christopher Strouse, MD, of the University of Iowa, Iowa City, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
There also were no significant differences in the outcomes between those who had extracranial radiation and those who had intracranial radiation (HRs for PFS and OS, respectively, 0.91 and 1.19), or (on univariate analysis), between those receiving any vs. no intracranial radiation therapy (HRs for PFS and OS, respectively, 0.92 and 0.98), Dr. Strouse said.
The patients who received extracranial radiation therapy had lower lymphocyte counts at the time of anti-PD-1/PD-L1 therapy initiation vs. those who received only radiation therapy (mean lymphocyte count, 809 vs. 1,519), and those who received intracranial radiation therapy were younger than those who did not (median age, 59 vs. 65 years), but the groups were similar with respect to other variables, including gender, histology, performance status, smoking history, KRAS mutation, and number of prior lines of systemic therapies. Anti-PD-1/PD-L1 therapies are promising treatment options for metastatic non–small cell lung cancer, and combining these agents with other immune-modulating therapies may enhance their efficacy and lead to a greater proportion of patients with responses to these treatments, Dr. Strouse noted.
“It’s known that immune response depends on a lot of steps, even beyond the PD-1/PD-L1 axis, and one possible explanation for some of these patients [not responding] may be that there is some failure along the way in some other step,” he said. “Our hypothesis was that radiation therapy would be helpful in overcoming some of these barriers.”
However, in this study, which is limited by small sample size and single-institution retrospective design, no such effect was identified.
The findings conflict with some larger studies, including the recently-reported PACIFIC study, which showed a significant PFS benefit in lung cancer patients who received chemoradiation therapy followed by treatment with the PD-L1 inhibitor durvalumab.
Dr. Strouse said he looks forward to seeing further reports looking into the effects of radiation therapy at different doses and timing.
Invited discussant Heather Wakelee, MD, of Stanford (Calif.) University, also stressed the limitations of the University of Iowa study, and noted that while there are many unanswered questions, findings such as those from the PACIFIC trial show that radiation and PD-L1 inhibition is here to stay.
“It appears safe; there will be more coming,” she said.
Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
CHICAGO – Exposure to radiation therapy prior to PD-1/PD-L1 therapy was not associated with improved outcomes in a retrospective review of 66 lung cancer patients.
The patients had stage IIIB or IV non–small cell lung cancer, median age of 64 years, received at least 6 weeks of single-agent anti-PD-1/PD-L1 therapy in the second-line setting or beyond, and had survived at least 8 weeks from immunotherapy initiation. Compared with 13 patients who received no radiation therapy, the 53 who received any prior radiation therapy – including 44 with extracranial radiation and 22 with intracranial radiation – did not differ significantly with respect to progression-free survival (median 4-5 months; hazard ratio, 0.83), or overall survival (median of about 12 months in both groups; HR, 0.96), Christopher Strouse, MD, of the University of Iowa, Iowa City, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
There also were no significant differences in the outcomes between those who had extracranial radiation and those who had intracranial radiation (HRs for PFS and OS, respectively, 0.91 and 1.19), or (on univariate analysis), between those receiving any vs. no intracranial radiation therapy (HRs for PFS and OS, respectively, 0.92 and 0.98), Dr. Strouse said.
The patients who received extracranial radiation therapy had lower lymphocyte counts at the time of anti-PD-1/PD-L1 therapy initiation vs. those who received only radiation therapy (mean lymphocyte count, 809 vs. 1,519), and those who received intracranial radiation therapy were younger than those who did not (median age, 59 vs. 65 years), but the groups were similar with respect to other variables, including gender, histology, performance status, smoking history, KRAS mutation, and number of prior lines of systemic therapies. Anti-PD-1/PD-L1 therapies are promising treatment options for metastatic non–small cell lung cancer, and combining these agents with other immune-modulating therapies may enhance their efficacy and lead to a greater proportion of patients with responses to these treatments, Dr. Strouse noted.
“It’s known that immune response depends on a lot of steps, even beyond the PD-1/PD-L1 axis, and one possible explanation for some of these patients [not responding] may be that there is some failure along the way in some other step,” he said. “Our hypothesis was that radiation therapy would be helpful in overcoming some of these barriers.”
However, in this study, which is limited by small sample size and single-institution retrospective design, no such effect was identified.
The findings conflict with some larger studies, including the recently-reported PACIFIC study, which showed a significant PFS benefit in lung cancer patients who received chemoradiation therapy followed by treatment with the PD-L1 inhibitor durvalumab.
Dr. Strouse said he looks forward to seeing further reports looking into the effects of radiation therapy at different doses and timing.
Invited discussant Heather Wakelee, MD, of Stanford (Calif.) University, also stressed the limitations of the University of Iowa study, and noted that while there are many unanswered questions, findings such as those from the PACIFIC trial show that radiation and PD-L1 inhibition is here to stay.
“It appears safe; there will be more coming,” she said.
Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
CHICAGO – Exposure to radiation therapy prior to PD-1/PD-L1 therapy was not associated with improved outcomes in a retrospective review of 66 lung cancer patients.
The patients had stage IIIB or IV non–small cell lung cancer, median age of 64 years, received at least 6 weeks of single-agent anti-PD-1/PD-L1 therapy in the second-line setting or beyond, and had survived at least 8 weeks from immunotherapy initiation. Compared with 13 patients who received no radiation therapy, the 53 who received any prior radiation therapy – including 44 with extracranial radiation and 22 with intracranial radiation – did not differ significantly with respect to progression-free survival (median 4-5 months; hazard ratio, 0.83), or overall survival (median of about 12 months in both groups; HR, 0.96), Christopher Strouse, MD, of the University of Iowa, Iowa City, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
There also were no significant differences in the outcomes between those who had extracranial radiation and those who had intracranial radiation (HRs for PFS and OS, respectively, 0.91 and 1.19), or (on univariate analysis), between those receiving any vs. no intracranial radiation therapy (HRs for PFS and OS, respectively, 0.92 and 0.98), Dr. Strouse said.
The patients who received extracranial radiation therapy had lower lymphocyte counts at the time of anti-PD-1/PD-L1 therapy initiation vs. those who received only radiation therapy (mean lymphocyte count, 809 vs. 1,519), and those who received intracranial radiation therapy were younger than those who did not (median age, 59 vs. 65 years), but the groups were similar with respect to other variables, including gender, histology, performance status, smoking history, KRAS mutation, and number of prior lines of systemic therapies. Anti-PD-1/PD-L1 therapies are promising treatment options for metastatic non–small cell lung cancer, and combining these agents with other immune-modulating therapies may enhance their efficacy and lead to a greater proportion of patients with responses to these treatments, Dr. Strouse noted.
“It’s known that immune response depends on a lot of steps, even beyond the PD-1/PD-L1 axis, and one possible explanation for some of these patients [not responding] may be that there is some failure along the way in some other step,” he said. “Our hypothesis was that radiation therapy would be helpful in overcoming some of these barriers.”
However, in this study, which is limited by small sample size and single-institution retrospective design, no such effect was identified.
The findings conflict with some larger studies, including the recently-reported PACIFIC study, which showed a significant PFS benefit in lung cancer patients who received chemoradiation therapy followed by treatment with the PD-L1 inhibitor durvalumab.
Dr. Strouse said he looks forward to seeing further reports looking into the effects of radiation therapy at different doses and timing.
Invited discussant Heather Wakelee, MD, of Stanford (Calif.) University, also stressed the limitations of the University of Iowa study, and noted that while there are many unanswered questions, findings such as those from the PACIFIC trial show that radiation and PD-L1 inhibition is here to stay.
“It appears safe; there will be more coming,” she said.
Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
AT A SYMPOSIUM IN THORACIC ONCOLOGY
Key clinical point:
Major finding: PFS and OS did not differ significantly between patients who did and did not receive prior radiation therapy (HRs for PFS and OS, respectively, 0.83 and 0.96).
Data source: A retrospective review of 66 patients.
Disclosures: Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
CRP may predict survival after immunotherapy for lung cancer
CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.
In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.
The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.
Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.
The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.
However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.
Dr. Naqash reported having no disclosures.
CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.
In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.
The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.
Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.
The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.
However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.
Dr. Naqash reported having no disclosures.
CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.
In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.
The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.
Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.
The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.
However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.
Dr. Naqash reported having no disclosures.
AT A SYMPOSIUM IN THORACIC ONCOLOGY
Key clinical point:
Major finding: Median overall survival after immunotherapy: 9.3 months vs. 2.7 months with CRP of 50 mg/L or less vs. above 50 mg/L.
Data source: A retrospective study of 99 patients.
Disclosures: Dr. Naqash reported having no disclosures.
Tocilizumab looks promising for corticosteroid refractory anti-PD-1-related adverse events
CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.
Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.
There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.
“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.
At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.
Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.
“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.
The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.
Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.
C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.
Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.
“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.
Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”
Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.
“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.
However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”
Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.
Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.
There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.
“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.
At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.
Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.
“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.
The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.
Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.
C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.
Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.
“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.
Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”
Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.
“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.
However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”
Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.
Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.
There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.
“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.
At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.
Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.
“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.
The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.
Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.
C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.
Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.
“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.
Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”
Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.
“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.
However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”
Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
AT A SYMPOSIUM IN THORACIC ONCOLOGY
Key clinical point:
Major finding: Twenty-seven of 34 patients treated with tocilizumab experienced clinical improvement.
Data source: A review of 87 patients.
Disclosures: Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
New data prompt update to ACC guidance on nonstatin LDL lowering
The American College of Cardiology Task Force on Expert Consensus Decision Pathways has released a “focused update” for the 2016 ACC Expert Consensus Decision Pathway (ECDP) on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease (ASCVD) risk.
The update was deemed by the ECDP writing committee to be desirable given the additional evidence and perspectives that have emerged since the publication of the 2016 version, particularly with respect to the efficacy and safety of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors for the secondary prevention of ASCVD, as well as the best use of ezetimibe in addition to statin therapy after acute coronary syndrome.
The ECDP algorithms endorse the four evidence-based statin benefit groups identified in the 2013 guidelines (adults aged 21 and older with clinical ASCVD, adults aged 21 and older with LDL-C of 190 mg/dL or greater, adults aged 40-75 years without ASCVD but with diabetes and with LDL-C of 70-189 mg/dL, and adults aged 40-75 without ASCVD or diabetes but with LDL-C of 70-189 mg/dL and an estimated 10-year risk for ASCVD of 7.5% or greater) and assume that the patient is currently taking or has attempted to take a statin, they noted.
Among the changes in the 2017 focused update are:
- Consideration of new randomized clinical trial data for the PCSK9 inhibitors evolocumab and bococizumab. Namely, they included results from the cardiovascular outcomes trials FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) and SPIRE-1 and SPIRE-2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), which were published in early 2017.
- An adjustment in the ECDP algorithms with respect to thresholds for consideration of net ASCVD risk reduction. The 2016 ECDP thresholds for risk reduction benefit were percent reduction in LDL-C with consideration of absolute LDL-C level in patients with clinical ASCVD, baseline LDL-C of 190 mg/dL or greater, and primary prevention. In patients with diabetes with or without clinical ASCVD, clinicians were allowed to consider absolute LDL-C and/or non-HDL-cholesterol levels. In the 2017 ECDP update, the thresholds are percent reduction in LDL-C with consideration of absolute LDL-C or non-HDL-C levels for patients in each of the four statin benefit groups. This change was based on the inclusion criteria of the FOURIER trial, the ongoing ODYSSEY Outcomes trial (Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment with Alirocumab), and the SPIRE-2 trial, all of which included non-HDL-C thresholds. “In alignment with these inclusion criteria, the 2017 Focused Update includes both LDL-C and non-HDL-C thresholds for evaluation of net ASCVD risk-reduction benefit when considering the addition of nonstatin therapies for patients in each of the four statin benefit groups” the update explained.
- An expansion of the threshold for consideration of net ASCVD risk-reduction benefit from a reduction of LDL C of at least 50%, as well as consideration of LDL-C less than 70 mg/dL or non-HDL-C less than 100 mg/dL for all patients (that is, both those with and those without comorbidities) who have clinical ASCVD and baseline LDL-C of 70-189 mg/dL. The 2016 ECDP had different thresholds for those with versus those without comorbidities. This change was based on findings from the FOURIER trial and the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).“Based on consideration of all available evidence, the consensus of the writing committee members is that lower LDL-C levels are safe and optimal in patients with clinical ASCVD due to [their] increased risk of recurrent events,” they said.
- An expanded recommendation on the use of ezetimibe and PCSK9 inhibition. The 2016 ECDP stated that “if a decision is made to proceed with the addition of nonstatin therapy to maximally tolerated statin therapy, it is reasonable to consider the addition of ezetimibe as the initial agent and a PCSK9 inhibitor as the second agent.” However, based on the FOURIER findings, the ongoing ODYSSEY Outcomes trial, and the IMPROVE-IT trial, the 2017 Focused Update states that, if such a decision is made in patients with clinical ASCVD with comorbidities and baseline LDL-C of 70-189 mg/dL, it is reasonable to weigh the addition of either ezetimibe or a PCSK9 inhibitor in light of “considerations of the additional percent LDL-C reduction desired, patient preferences, costs, route of administration, and other factors.” The update also spells out considerations that may favor the initial choice of ezetimibe versus a PCSK9 inhibitor (such as requiring less than 25% additional lowering of LDL-C, an age of over 75 years, cost, and other patient factors and preferences) .
- Additional factors, based on the FOURIER trial results and inclusion criteria, that may be considered for the identification of higher-risk patients with clinical ASCVD. The 2016 ECDP included on this list diabetes, a recent ASCVD event, an ASCVD event while already taking a statin, poorly controlled other major ASCVD risk factors, elevated lipoprotein, chronic kidney disease, symptomatic heart failure, maintenance hemodialysis, and baseline LDL-C of at least 190 mg/dL not due to secondary causes. The 2017 update added being 65 years or older, prior MI or nonhemorrhagic stroke, current daily cigarette smoking, symptomatic peripheral artery disease with prior MI or stroke, history of non-MI related coronary revascularization, residual coronary artery disease with at least 40% stenosis in at least two large vessels, HDL-C less than 40 mg/dL for men and less than 50 mg/dL for women, high-sensitivity C-reactive protein greater than 2 mg/L, and metabolic syndrome.
The content of the full ECDP has been changed in accordance with these updates and now includes more extensive and detailed guidance for decision making – both in the text and in treatment algorithms.
Aspects that remain unchanged include the decision pathways and algorithms for the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C less than 190 mg/dL or in those without ASCVD and LDL-C of 190 mg/dL or greater unattributable to secondary causes.
In addition to other changes made for the purpose of clarification and consistency, recommendations regarding bile acid–sequestrant use were downgraded; these are now only recommended as optional secondary agents for consideration in patients who cannot tolerate ezetimibe.
“[These] recommendations attempt to provide practical guidance for clinicians and patients regarding the use of nonstatin therapies to further reduce ASCVD risk in situations not covered by the guideline until such time as the scientific evidence base expands and cardiovascular outcomes trials are completed with new agents for ASCVD risk reduction,” the committee concluded.
Dr. Lloyd-Jones reported having no disclosures.
The American College of Cardiology Task Force on Expert Consensus Decision Pathways has released a “focused update” for the 2016 ACC Expert Consensus Decision Pathway (ECDP) on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease (ASCVD) risk.
The update was deemed by the ECDP writing committee to be desirable given the additional evidence and perspectives that have emerged since the publication of the 2016 version, particularly with respect to the efficacy and safety of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors for the secondary prevention of ASCVD, as well as the best use of ezetimibe in addition to statin therapy after acute coronary syndrome.
The ECDP algorithms endorse the four evidence-based statin benefit groups identified in the 2013 guidelines (adults aged 21 and older with clinical ASCVD, adults aged 21 and older with LDL-C of 190 mg/dL or greater, adults aged 40-75 years without ASCVD but with diabetes and with LDL-C of 70-189 mg/dL, and adults aged 40-75 without ASCVD or diabetes but with LDL-C of 70-189 mg/dL and an estimated 10-year risk for ASCVD of 7.5% or greater) and assume that the patient is currently taking or has attempted to take a statin, they noted.
Among the changes in the 2017 focused update are:
- Consideration of new randomized clinical trial data for the PCSK9 inhibitors evolocumab and bococizumab. Namely, they included results from the cardiovascular outcomes trials FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) and SPIRE-1 and SPIRE-2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), which were published in early 2017.
- An adjustment in the ECDP algorithms with respect to thresholds for consideration of net ASCVD risk reduction. The 2016 ECDP thresholds for risk reduction benefit were percent reduction in LDL-C with consideration of absolute LDL-C level in patients with clinical ASCVD, baseline LDL-C of 190 mg/dL or greater, and primary prevention. In patients with diabetes with or without clinical ASCVD, clinicians were allowed to consider absolute LDL-C and/or non-HDL-cholesterol levels. In the 2017 ECDP update, the thresholds are percent reduction in LDL-C with consideration of absolute LDL-C or non-HDL-C levels for patients in each of the four statin benefit groups. This change was based on the inclusion criteria of the FOURIER trial, the ongoing ODYSSEY Outcomes trial (Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment with Alirocumab), and the SPIRE-2 trial, all of which included non-HDL-C thresholds. “In alignment with these inclusion criteria, the 2017 Focused Update includes both LDL-C and non-HDL-C thresholds for evaluation of net ASCVD risk-reduction benefit when considering the addition of nonstatin therapies for patients in each of the four statin benefit groups” the update explained.
- An expansion of the threshold for consideration of net ASCVD risk-reduction benefit from a reduction of LDL C of at least 50%, as well as consideration of LDL-C less than 70 mg/dL or non-HDL-C less than 100 mg/dL for all patients (that is, both those with and those without comorbidities) who have clinical ASCVD and baseline LDL-C of 70-189 mg/dL. The 2016 ECDP had different thresholds for those with versus those without comorbidities. This change was based on findings from the FOURIER trial and the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).“Based on consideration of all available evidence, the consensus of the writing committee members is that lower LDL-C levels are safe and optimal in patients with clinical ASCVD due to [their] increased risk of recurrent events,” they said.
- An expanded recommendation on the use of ezetimibe and PCSK9 inhibition. The 2016 ECDP stated that “if a decision is made to proceed with the addition of nonstatin therapy to maximally tolerated statin therapy, it is reasonable to consider the addition of ezetimibe as the initial agent and a PCSK9 inhibitor as the second agent.” However, based on the FOURIER findings, the ongoing ODYSSEY Outcomes trial, and the IMPROVE-IT trial, the 2017 Focused Update states that, if such a decision is made in patients with clinical ASCVD with comorbidities and baseline LDL-C of 70-189 mg/dL, it is reasonable to weigh the addition of either ezetimibe or a PCSK9 inhibitor in light of “considerations of the additional percent LDL-C reduction desired, patient preferences, costs, route of administration, and other factors.” The update also spells out considerations that may favor the initial choice of ezetimibe versus a PCSK9 inhibitor (such as requiring less than 25% additional lowering of LDL-C, an age of over 75 years, cost, and other patient factors and preferences) .
- Additional factors, based on the FOURIER trial results and inclusion criteria, that may be considered for the identification of higher-risk patients with clinical ASCVD. The 2016 ECDP included on this list diabetes, a recent ASCVD event, an ASCVD event while already taking a statin, poorly controlled other major ASCVD risk factors, elevated lipoprotein, chronic kidney disease, symptomatic heart failure, maintenance hemodialysis, and baseline LDL-C of at least 190 mg/dL not due to secondary causes. The 2017 update added being 65 years or older, prior MI or nonhemorrhagic stroke, current daily cigarette smoking, symptomatic peripheral artery disease with prior MI or stroke, history of non-MI related coronary revascularization, residual coronary artery disease with at least 40% stenosis in at least two large vessels, HDL-C less than 40 mg/dL for men and less than 50 mg/dL for women, high-sensitivity C-reactive protein greater than 2 mg/L, and metabolic syndrome.
The content of the full ECDP has been changed in accordance with these updates and now includes more extensive and detailed guidance for decision making – both in the text and in treatment algorithms.
Aspects that remain unchanged include the decision pathways and algorithms for the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C less than 190 mg/dL or in those without ASCVD and LDL-C of 190 mg/dL or greater unattributable to secondary causes.
In addition to other changes made for the purpose of clarification and consistency, recommendations regarding bile acid–sequestrant use were downgraded; these are now only recommended as optional secondary agents for consideration in patients who cannot tolerate ezetimibe.
“[These] recommendations attempt to provide practical guidance for clinicians and patients regarding the use of nonstatin therapies to further reduce ASCVD risk in situations not covered by the guideline until such time as the scientific evidence base expands and cardiovascular outcomes trials are completed with new agents for ASCVD risk reduction,” the committee concluded.
Dr. Lloyd-Jones reported having no disclosures.
The American College of Cardiology Task Force on Expert Consensus Decision Pathways has released a “focused update” for the 2016 ACC Expert Consensus Decision Pathway (ECDP) on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease (ASCVD) risk.
The update was deemed by the ECDP writing committee to be desirable given the additional evidence and perspectives that have emerged since the publication of the 2016 version, particularly with respect to the efficacy and safety of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors for the secondary prevention of ASCVD, as well as the best use of ezetimibe in addition to statin therapy after acute coronary syndrome.
The ECDP algorithms endorse the four evidence-based statin benefit groups identified in the 2013 guidelines (adults aged 21 and older with clinical ASCVD, adults aged 21 and older with LDL-C of 190 mg/dL or greater, adults aged 40-75 years without ASCVD but with diabetes and with LDL-C of 70-189 mg/dL, and adults aged 40-75 without ASCVD or diabetes but with LDL-C of 70-189 mg/dL and an estimated 10-year risk for ASCVD of 7.5% or greater) and assume that the patient is currently taking or has attempted to take a statin, they noted.
Among the changes in the 2017 focused update are:
- Consideration of new randomized clinical trial data for the PCSK9 inhibitors evolocumab and bococizumab. Namely, they included results from the cardiovascular outcomes trials FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) and SPIRE-1 and SPIRE-2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), which were published in early 2017.
- An adjustment in the ECDP algorithms with respect to thresholds for consideration of net ASCVD risk reduction. The 2016 ECDP thresholds for risk reduction benefit were percent reduction in LDL-C with consideration of absolute LDL-C level in patients with clinical ASCVD, baseline LDL-C of 190 mg/dL or greater, and primary prevention. In patients with diabetes with or without clinical ASCVD, clinicians were allowed to consider absolute LDL-C and/or non-HDL-cholesterol levels. In the 2017 ECDP update, the thresholds are percent reduction in LDL-C with consideration of absolute LDL-C or non-HDL-C levels for patients in each of the four statin benefit groups. This change was based on the inclusion criteria of the FOURIER trial, the ongoing ODYSSEY Outcomes trial (Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment with Alirocumab), and the SPIRE-2 trial, all of which included non-HDL-C thresholds. “In alignment with these inclusion criteria, the 2017 Focused Update includes both LDL-C and non-HDL-C thresholds for evaluation of net ASCVD risk-reduction benefit when considering the addition of nonstatin therapies for patients in each of the four statin benefit groups” the update explained.
- An expansion of the threshold for consideration of net ASCVD risk-reduction benefit from a reduction of LDL C of at least 50%, as well as consideration of LDL-C less than 70 mg/dL or non-HDL-C less than 100 mg/dL for all patients (that is, both those with and those without comorbidities) who have clinical ASCVD and baseline LDL-C of 70-189 mg/dL. The 2016 ECDP had different thresholds for those with versus those without comorbidities. This change was based on findings from the FOURIER trial and the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).“Based on consideration of all available evidence, the consensus of the writing committee members is that lower LDL-C levels are safe and optimal in patients with clinical ASCVD due to [their] increased risk of recurrent events,” they said.
- An expanded recommendation on the use of ezetimibe and PCSK9 inhibition. The 2016 ECDP stated that “if a decision is made to proceed with the addition of nonstatin therapy to maximally tolerated statin therapy, it is reasonable to consider the addition of ezetimibe as the initial agent and a PCSK9 inhibitor as the second agent.” However, based on the FOURIER findings, the ongoing ODYSSEY Outcomes trial, and the IMPROVE-IT trial, the 2017 Focused Update states that, if such a decision is made in patients with clinical ASCVD with comorbidities and baseline LDL-C of 70-189 mg/dL, it is reasonable to weigh the addition of either ezetimibe or a PCSK9 inhibitor in light of “considerations of the additional percent LDL-C reduction desired, patient preferences, costs, route of administration, and other factors.” The update also spells out considerations that may favor the initial choice of ezetimibe versus a PCSK9 inhibitor (such as requiring less than 25% additional lowering of LDL-C, an age of over 75 years, cost, and other patient factors and preferences) .
- Additional factors, based on the FOURIER trial results and inclusion criteria, that may be considered for the identification of higher-risk patients with clinical ASCVD. The 2016 ECDP included on this list diabetes, a recent ASCVD event, an ASCVD event while already taking a statin, poorly controlled other major ASCVD risk factors, elevated lipoprotein, chronic kidney disease, symptomatic heart failure, maintenance hemodialysis, and baseline LDL-C of at least 190 mg/dL not due to secondary causes. The 2017 update added being 65 years or older, prior MI or nonhemorrhagic stroke, current daily cigarette smoking, symptomatic peripheral artery disease with prior MI or stroke, history of non-MI related coronary revascularization, residual coronary artery disease with at least 40% stenosis in at least two large vessels, HDL-C less than 40 mg/dL for men and less than 50 mg/dL for women, high-sensitivity C-reactive protein greater than 2 mg/L, and metabolic syndrome.
The content of the full ECDP has been changed in accordance with these updates and now includes more extensive and detailed guidance for decision making – both in the text and in treatment algorithms.
Aspects that remain unchanged include the decision pathways and algorithms for the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C less than 190 mg/dL or in those without ASCVD and LDL-C of 190 mg/dL or greater unattributable to secondary causes.
In addition to other changes made for the purpose of clarification and consistency, recommendations regarding bile acid–sequestrant use were downgraded; these are now only recommended as optional secondary agents for consideration in patients who cannot tolerate ezetimibe.
“[These] recommendations attempt to provide practical guidance for clinicians and patients regarding the use of nonstatin therapies to further reduce ASCVD risk in situations not covered by the guideline until such time as the scientific evidence base expands and cardiovascular outcomes trials are completed with new agents for ASCVD risk reduction,” the committee concluded.
Dr. Lloyd-Jones reported having no disclosures.
FROM JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
PROTECT trial: No DFS benefit with adjuvant pazopanib for high-risk RCC
Adjuvant pazopanib provided no disease-free survival benefit compared with placebo in the randomized phase 3 PROTECT trial of patients with locally advanced renal cell carcinoma at high risk for relapse after nephrectomy.
In the primary analysis for disease-free survival among 571 patients treated for 1 year with 600 mg of pazopanib and 564 who received placebo, no significant improvement was seen with pazopanib (hazard ratio, 0.86). In a follow-up analysis 12 months later, the hazard ratio was 0.94. Secondary analysis in 403 additional patients who were treated with 800 mg of pazopanib before the dose was lowered to 600 mg due to intolerance and toxicity attrition showed a benefit with pazopanib (HR, 0.69), but this group represented only a third of the study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues. The study results were published online in the Journal of Clinical Oncology.
Common adverse events leading to treatment discontinuation included increased alanine transaminase and aspartate transaminase levels, which occurred in 16% and 5% of patients treated with 600 mg, respectively, and in 18% and 7% of patients treated with 800 mg, respectively. Four grade 5 adverse events occurred in the pazopanib groups (vs. 2 in the placebo group), and one of the deaths (in a patient who received 800 mg dosing) involved cardiomyopathy that was considered to be related to treatment, the investigators said (J Clin Oncol. 2017 Sep 13. doi: 10.1200/JCO.2017.73.5324).
The study comprised adults with resected pT2 or pT3 and greater disease, including N1, clear cell renal cell carcinoma, who were enrolled between Dec. 9, 2010, and Sept. 10, 2013, from 263 centers in 26 countries. Primary analysis was done after 350 disease-free events occurred in the intent-to-treat population receiving 600 mg.
The difference in treatment effect between those receiving 600 mg and 800 mg of pazopanib could be explained by the different starting dose, or by better performance of the placebo arm in the 600 mg group, the investigators noted.
As for overall survival, the results are inconclusive, because the data are not mature, they said.
Novartis supported the study. Dr. Mercer reported consulting or advisory roles with Pfizer, Novartis, Eisai, and Exelixis, and research funding to his institution from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech. Numerous coauthors also reported financial relationships with pharmaceutical companies.
Adjuvant pazopanib provided no disease-free survival benefit compared with placebo in the randomized phase 3 PROTECT trial of patients with locally advanced renal cell carcinoma at high risk for relapse after nephrectomy.
In the primary analysis for disease-free survival among 571 patients treated for 1 year with 600 mg of pazopanib and 564 who received placebo, no significant improvement was seen with pazopanib (hazard ratio, 0.86). In a follow-up analysis 12 months later, the hazard ratio was 0.94. Secondary analysis in 403 additional patients who were treated with 800 mg of pazopanib before the dose was lowered to 600 mg due to intolerance and toxicity attrition showed a benefit with pazopanib (HR, 0.69), but this group represented only a third of the study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues. The study results were published online in the Journal of Clinical Oncology.
Common adverse events leading to treatment discontinuation included increased alanine transaminase and aspartate transaminase levels, which occurred in 16% and 5% of patients treated with 600 mg, respectively, and in 18% and 7% of patients treated with 800 mg, respectively. Four grade 5 adverse events occurred in the pazopanib groups (vs. 2 in the placebo group), and one of the deaths (in a patient who received 800 mg dosing) involved cardiomyopathy that was considered to be related to treatment, the investigators said (J Clin Oncol. 2017 Sep 13. doi: 10.1200/JCO.2017.73.5324).
The study comprised adults with resected pT2 or pT3 and greater disease, including N1, clear cell renal cell carcinoma, who were enrolled between Dec. 9, 2010, and Sept. 10, 2013, from 263 centers in 26 countries. Primary analysis was done after 350 disease-free events occurred in the intent-to-treat population receiving 600 mg.
The difference in treatment effect between those receiving 600 mg and 800 mg of pazopanib could be explained by the different starting dose, or by better performance of the placebo arm in the 600 mg group, the investigators noted.
As for overall survival, the results are inconclusive, because the data are not mature, they said.
Novartis supported the study. Dr. Mercer reported consulting or advisory roles with Pfizer, Novartis, Eisai, and Exelixis, and research funding to his institution from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech. Numerous coauthors also reported financial relationships with pharmaceutical companies.
Adjuvant pazopanib provided no disease-free survival benefit compared with placebo in the randomized phase 3 PROTECT trial of patients with locally advanced renal cell carcinoma at high risk for relapse after nephrectomy.
In the primary analysis for disease-free survival among 571 patients treated for 1 year with 600 mg of pazopanib and 564 who received placebo, no significant improvement was seen with pazopanib (hazard ratio, 0.86). In a follow-up analysis 12 months later, the hazard ratio was 0.94. Secondary analysis in 403 additional patients who were treated with 800 mg of pazopanib before the dose was lowered to 600 mg due to intolerance and toxicity attrition showed a benefit with pazopanib (HR, 0.69), but this group represented only a third of the study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues. The study results were published online in the Journal of Clinical Oncology.
Common adverse events leading to treatment discontinuation included increased alanine transaminase and aspartate transaminase levels, which occurred in 16% and 5% of patients treated with 600 mg, respectively, and in 18% and 7% of patients treated with 800 mg, respectively. Four grade 5 adverse events occurred in the pazopanib groups (vs. 2 in the placebo group), and one of the deaths (in a patient who received 800 mg dosing) involved cardiomyopathy that was considered to be related to treatment, the investigators said (J Clin Oncol. 2017 Sep 13. doi: 10.1200/JCO.2017.73.5324).
The study comprised adults with resected pT2 or pT3 and greater disease, including N1, clear cell renal cell carcinoma, who were enrolled between Dec. 9, 2010, and Sept. 10, 2013, from 263 centers in 26 countries. Primary analysis was done after 350 disease-free events occurred in the intent-to-treat population receiving 600 mg.
The difference in treatment effect between those receiving 600 mg and 800 mg of pazopanib could be explained by the different starting dose, or by better performance of the placebo arm in the 600 mg group, the investigators noted.
As for overall survival, the results are inconclusive, because the data are not mature, they said.
Novartis supported the study. Dr. Mercer reported consulting or advisory roles with Pfizer, Novartis, Eisai, and Exelixis, and research funding to his institution from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech. Numerous coauthors also reported financial relationships with pharmaceutical companies.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: In the primary analysis for disease-free survival, no significant improvement was seen with pazopanib vs. placebo (hazard ratio, 0.86).
Data source: The phase 3 PROTECT study of 1,538 patients.
Disclosures: Novartis supported the study. Dr. Mercer reported consulting or advisory roles with Pfizer, Novartis, Eisai, and Exelixis, and research funding to his institution from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech. Numerous coauthors also reported financial relationships with pharmaceutical companies.
KW-2478 examined as novel add-on therapy for myeloma
Bortezomib and KW-2478, a novel nonansamycin heat shock protein 90 (Hsp90) inhibitor, had modest activity and was well tolerated in an open-label phase 1/2 study of patients with relapsed or refractory multiple myeloma.
The objective response rate in 79 evaluable patients treated with the combination was 39.2%, and the clinical benefit rate was 51.9%. Median progression-free survival was 6.7 months, and median duration of response was 5.5 months, according to a report by Jamie Cavenagh, MD, of St. Bartholomew’s Hospital, West Smithfield, London, and colleagues. The results were published online in the British Journal of Cancer.
KW-2478 showed synergistic antitumor activity with bortezomib in preclinical in vitro and in vivo studies, and the recommended phase 2 intravenous dosage of 175 mg/m2, along with 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 of each 21-day cycle (up to eight cycles) in the current study was determined by phase 1 dose escalation; the maximum tolerated dose was not reached.
Although the antimyeloma activity of this novel treatment combination was relatively modest, the tolerability and apparent lack of overlapping toxicity suggest it deserves further exploration, including with alternate dosing schedules and combinations, for the treatment of relapsed/refractory multiple myeloma, the investigators concluded, noting that KW-2478 should also be studied in combination with other antimyeloma agents.
Kyowa Kirin Pharmaceutical Development Inc. funded the study. Dr. Cavenagh reported having no disclosures. Several other authors reported employment by the sponsor or by Kyowa Hakko Kirin Co. Ltd. Another, K. Yong, MD, reported receiving support from the National Institute for Health Research.
Bortezomib and KW-2478, a novel nonansamycin heat shock protein 90 (Hsp90) inhibitor, had modest activity and was well tolerated in an open-label phase 1/2 study of patients with relapsed or refractory multiple myeloma.
The objective response rate in 79 evaluable patients treated with the combination was 39.2%, and the clinical benefit rate was 51.9%. Median progression-free survival was 6.7 months, and median duration of response was 5.5 months, according to a report by Jamie Cavenagh, MD, of St. Bartholomew’s Hospital, West Smithfield, London, and colleagues. The results were published online in the British Journal of Cancer.
KW-2478 showed synergistic antitumor activity with bortezomib in preclinical in vitro and in vivo studies, and the recommended phase 2 intravenous dosage of 175 mg/m2, along with 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 of each 21-day cycle (up to eight cycles) in the current study was determined by phase 1 dose escalation; the maximum tolerated dose was not reached.
Although the antimyeloma activity of this novel treatment combination was relatively modest, the tolerability and apparent lack of overlapping toxicity suggest it deserves further exploration, including with alternate dosing schedules and combinations, for the treatment of relapsed/refractory multiple myeloma, the investigators concluded, noting that KW-2478 should also be studied in combination with other antimyeloma agents.
Kyowa Kirin Pharmaceutical Development Inc. funded the study. Dr. Cavenagh reported having no disclosures. Several other authors reported employment by the sponsor or by Kyowa Hakko Kirin Co. Ltd. Another, K. Yong, MD, reported receiving support from the National Institute for Health Research.
Bortezomib and KW-2478, a novel nonansamycin heat shock protein 90 (Hsp90) inhibitor, had modest activity and was well tolerated in an open-label phase 1/2 study of patients with relapsed or refractory multiple myeloma.
The objective response rate in 79 evaluable patients treated with the combination was 39.2%, and the clinical benefit rate was 51.9%. Median progression-free survival was 6.7 months, and median duration of response was 5.5 months, according to a report by Jamie Cavenagh, MD, of St. Bartholomew’s Hospital, West Smithfield, London, and colleagues. The results were published online in the British Journal of Cancer.
KW-2478 showed synergistic antitumor activity with bortezomib in preclinical in vitro and in vivo studies, and the recommended phase 2 intravenous dosage of 175 mg/m2, along with 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 of each 21-day cycle (up to eight cycles) in the current study was determined by phase 1 dose escalation; the maximum tolerated dose was not reached.
Although the antimyeloma activity of this novel treatment combination was relatively modest, the tolerability and apparent lack of overlapping toxicity suggest it deserves further exploration, including with alternate dosing schedules and combinations, for the treatment of relapsed/refractory multiple myeloma, the investigators concluded, noting that KW-2478 should also be studied in combination with other antimyeloma agents.
Kyowa Kirin Pharmaceutical Development Inc. funded the study. Dr. Cavenagh reported having no disclosures. Several other authors reported employment by the sponsor or by Kyowa Hakko Kirin Co. Ltd. Another, K. Yong, MD, reported receiving support from the National Institute for Health Research.
FROM THE BRITISH JOURNAL OF CANCER
Key clinical point:
Major finding: The objective response rate was 39.2%, and the clinical benefit rate was 51.9%.
Data source: An open-label phase 1/2 study of 95 patients.
Disclosures: Kyowa Kirin Pharmaceutical Development Inc. funded the study. Dr. Cavenagh reported having no disclosures. Several other authors reported employment by the sponsor or by Kyowa Hakko Kirin Co. Ltd. Another, K. Yong, MD, reported receiving support from the National Institute for Health Research.
WHI hormone trials offer reassurance on long-term mortality risk
Postmenopausal women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years, or with CEE alone for a median of 7.2 years had no increased risk of all-cause, cardiovascular, or cancer mortality over a cumulative follow-up of 18 years, according to the latest report from the Women’s Health Initiative hormone therapy trials.
All-cause mortality among the 27,347 participants in the two randomized, double-blind, placebo-controlled trials was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99), JoAnn E. Manson, MD, Harvard Medical School, Boston, and her colleagues reported.
For those who received CEE plus MPA, the hazard ratio was 1.02, while for CEE alone the hazard ratio was 0.94 (JAMA. 2017 Sep;318[10]:927-38).
Cardiovascular mortality among the pooled cohort was 8.9% with hormone therapy and 9.0% with placebo (HR, 1.00), and total cancer mortality was 8.2% and 8.0%, respectively (HR, 1.03). Mortality from other causes was 10.0% with hormone therapy, compared with 10.7% with placebo (HR, 0.95). The results did not differ significantly between the trials, the investigators noted.
An analysis by age showed that women aged 50-59 years tended to have lower hazard ratios for mortality from cardiovascular disease, cancer, and other causes during the intervention phases of the trials, but only the difference for “other” causes in the CEE-alone trial showed a statistically significant trend with age. This was influenced in part by adverse effects of the treatment in women aged 70-79 years. During cumulative follow-up, trends related to mortality across age groups were not statistically significantly different.
The trials included women aged 50-79 years who were enrolled between 1993 and 1998 and followed through 2014. Given the hormone-therapy-related risks identified in the CEE plus MPA and CEE-alone trials – which were stopped early because of increased risk of breast cancer/overall risks exceeding benefits, and for increased stroke risk, respectively – the absence of an increase in all-cause mortality during the intervention and cumulative follow-up phases of the trials is noteworthy, the investigators wrote.
“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate to severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” they wrote. “Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment.”
They added that “in clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”
The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no financial disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.
The findings from the Women’s Health Initiative hormone therapy trials as reported by Dr. Manson and her colleagues expand the understanding of the long-term risks and benefits of hormone therapy, which is an important issue for women around the world, Melissa A. McNeil, MD, wrote in an editorial.
The information will be helpful for counseling women considering whether to start hormone therapy, and “hopefully will alleviate concerns that many patients and physicians have about the initiation of hormone therapy,” she said, explaining that the effect of hormone therapy on cancer mortality, and especially on breast cancer mortality, has generated concern and reluctance to prescribe and take hormone therapy for troubling menopausal symptoms.
“The current report ... provides substantial reassurance for patients and physicians about this issue,” she said. “For women with troubling vasomotor symptoms, premature menopause, or early-onset osteoporosis, hormone therapy appears to be both safe and efficacious.”
While several questions remain, including about optimal duration of therapy, whether there is a difference in mortality by age and menopausal status at hormone therapy initiation, and if earlier initiation would provide additional benefits, the data “fully support the newly released 2017 hormone therapy position statement of the North American Menopause Society and are a welcome addition to current knowledge regarding hormone therapy administration,” she wrote.
Dr. McNeil is with the University of Pittsburgh. She reported having no financial disclosures. Her comments come from an accompanying editorial (JAMA. 2017 Sep;318[10]:911-13).
The findings from the Women’s Health Initiative hormone therapy trials as reported by Dr. Manson and her colleagues expand the understanding of the long-term risks and benefits of hormone therapy, which is an important issue for women around the world, Melissa A. McNeil, MD, wrote in an editorial.
The information will be helpful for counseling women considering whether to start hormone therapy, and “hopefully will alleviate concerns that many patients and physicians have about the initiation of hormone therapy,” she said, explaining that the effect of hormone therapy on cancer mortality, and especially on breast cancer mortality, has generated concern and reluctance to prescribe and take hormone therapy for troubling menopausal symptoms.
“The current report ... provides substantial reassurance for patients and physicians about this issue,” she said. “For women with troubling vasomotor symptoms, premature menopause, or early-onset osteoporosis, hormone therapy appears to be both safe and efficacious.”
While several questions remain, including about optimal duration of therapy, whether there is a difference in mortality by age and menopausal status at hormone therapy initiation, and if earlier initiation would provide additional benefits, the data “fully support the newly released 2017 hormone therapy position statement of the North American Menopause Society and are a welcome addition to current knowledge regarding hormone therapy administration,” she wrote.
Dr. McNeil is with the University of Pittsburgh. She reported having no financial disclosures. Her comments come from an accompanying editorial (JAMA. 2017 Sep;318[10]:911-13).
The findings from the Women’s Health Initiative hormone therapy trials as reported by Dr. Manson and her colleagues expand the understanding of the long-term risks and benefits of hormone therapy, which is an important issue for women around the world, Melissa A. McNeil, MD, wrote in an editorial.
The information will be helpful for counseling women considering whether to start hormone therapy, and “hopefully will alleviate concerns that many patients and physicians have about the initiation of hormone therapy,” she said, explaining that the effect of hormone therapy on cancer mortality, and especially on breast cancer mortality, has generated concern and reluctance to prescribe and take hormone therapy for troubling menopausal symptoms.
“The current report ... provides substantial reassurance for patients and physicians about this issue,” she said. “For women with troubling vasomotor symptoms, premature menopause, or early-onset osteoporosis, hormone therapy appears to be both safe and efficacious.”
While several questions remain, including about optimal duration of therapy, whether there is a difference in mortality by age and menopausal status at hormone therapy initiation, and if earlier initiation would provide additional benefits, the data “fully support the newly released 2017 hormone therapy position statement of the North American Menopause Society and are a welcome addition to current knowledge regarding hormone therapy administration,” she wrote.
Dr. McNeil is with the University of Pittsburgh. She reported having no financial disclosures. Her comments come from an accompanying editorial (JAMA. 2017 Sep;318[10]:911-13).
Postmenopausal women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years, or with CEE alone for a median of 7.2 years had no increased risk of all-cause, cardiovascular, or cancer mortality over a cumulative follow-up of 18 years, according to the latest report from the Women’s Health Initiative hormone therapy trials.
All-cause mortality among the 27,347 participants in the two randomized, double-blind, placebo-controlled trials was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99), JoAnn E. Manson, MD, Harvard Medical School, Boston, and her colleagues reported.
For those who received CEE plus MPA, the hazard ratio was 1.02, while for CEE alone the hazard ratio was 0.94 (JAMA. 2017 Sep;318[10]:927-38).
Cardiovascular mortality among the pooled cohort was 8.9% with hormone therapy and 9.0% with placebo (HR, 1.00), and total cancer mortality was 8.2% and 8.0%, respectively (HR, 1.03). Mortality from other causes was 10.0% with hormone therapy, compared with 10.7% with placebo (HR, 0.95). The results did not differ significantly between the trials, the investigators noted.
An analysis by age showed that women aged 50-59 years tended to have lower hazard ratios for mortality from cardiovascular disease, cancer, and other causes during the intervention phases of the trials, but only the difference for “other” causes in the CEE-alone trial showed a statistically significant trend with age. This was influenced in part by adverse effects of the treatment in women aged 70-79 years. During cumulative follow-up, trends related to mortality across age groups were not statistically significantly different.
The trials included women aged 50-79 years who were enrolled between 1993 and 1998 and followed through 2014. Given the hormone-therapy-related risks identified in the CEE plus MPA and CEE-alone trials – which were stopped early because of increased risk of breast cancer/overall risks exceeding benefits, and for increased stroke risk, respectively – the absence of an increase in all-cause mortality during the intervention and cumulative follow-up phases of the trials is noteworthy, the investigators wrote.
“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate to severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” they wrote. “Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment.”
They added that “in clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”
The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no financial disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.
Postmenopausal women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years, or with CEE alone for a median of 7.2 years had no increased risk of all-cause, cardiovascular, or cancer mortality over a cumulative follow-up of 18 years, according to the latest report from the Women’s Health Initiative hormone therapy trials.
All-cause mortality among the 27,347 participants in the two randomized, double-blind, placebo-controlled trials was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99), JoAnn E. Manson, MD, Harvard Medical School, Boston, and her colleagues reported.
For those who received CEE plus MPA, the hazard ratio was 1.02, while for CEE alone the hazard ratio was 0.94 (JAMA. 2017 Sep;318[10]:927-38).
Cardiovascular mortality among the pooled cohort was 8.9% with hormone therapy and 9.0% with placebo (HR, 1.00), and total cancer mortality was 8.2% and 8.0%, respectively (HR, 1.03). Mortality from other causes was 10.0% with hormone therapy, compared with 10.7% with placebo (HR, 0.95). The results did not differ significantly between the trials, the investigators noted.
An analysis by age showed that women aged 50-59 years tended to have lower hazard ratios for mortality from cardiovascular disease, cancer, and other causes during the intervention phases of the trials, but only the difference for “other” causes in the CEE-alone trial showed a statistically significant trend with age. This was influenced in part by adverse effects of the treatment in women aged 70-79 years. During cumulative follow-up, trends related to mortality across age groups were not statistically significantly different.
The trials included women aged 50-79 years who were enrolled between 1993 and 1998 and followed through 2014. Given the hormone-therapy-related risks identified in the CEE plus MPA and CEE-alone trials – which were stopped early because of increased risk of breast cancer/overall risks exceeding benefits, and for increased stroke risk, respectively – the absence of an increase in all-cause mortality during the intervention and cumulative follow-up phases of the trials is noteworthy, the investigators wrote.
“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate to severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” they wrote. “Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment.”
They added that “in clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”
The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no financial disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.
FROM JAMA
Key clinical point:
Major finding: All-cause mortality was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99).
Data source: The randomized, double-blind, placebo-controlled Women’s Health Initiative hormone therapy trials of 27,347 women.
Disclosures: The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.