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Targeted therapy brings fresh hope for small-cell lung cancer treatment
VIENNA – Rovalpituzumab tesirine, an antibody drug conjugate that targets delta-like protein 3, produced responses in a range of patients with previously treated small-cell lung cancer in a phase I study.
Responses to rovalpituzumab tesirine (Rova-T) were higher and more durable in patients with tumors positive for DLL3, a protein previously shown to be over-expressed in about 70% of small-cell lung cancers (SCLCs).
“DLL3 may be the first predictive biomarker associated with treatment efficacy in small-cell lung cancer,” Dr. M. Catherine Pietanza of Memorial Sloan Kettering Cancer Center, New York City, said during a presidential session at the European Cancer Congress 2015.
While SCLC is initially sensitive to chemotherapy and radiation, resistance develops quickly. Topotecan (Hycamtin) is the only approved agent in the second-line setting. None are available in the third-line setting and outcomes remain dismal, with 5-year survival rates of 6%, she said.
The study enrolled 73 patients with recurrent or progressive SCLC after first- or second-line therapy and administered escalating doses of rovalpituzumab tesirine (0.05 mg/kg to 0.8 mg/kg) once every 3 weeks. Confirmed responses were observed at the 0.2-mg/kg, 0.3-mg/kg, and 0.4-mg/kg dose levels.
The maximum tolerated dose was 0.4 mg/kg, but continued dosing revealed cumulative toxicities, most often serosal effusions, Dr. Pietanza said. The agent was also found to have a prolonged half-life, prompting the researchers to proceed with rovalpituzumab tesirine 0.2 mg/kg every 3 weeks and 0.3 mg/kg every 6 weeks in the phase Ib expansion cohorts.
The patients median age was 61 years and 56% were male. Of the 49 tumor samples available for analysis, 71% were positive for high DLL3 expression using an H score cutoff of at least 180 on a scale of 300.
For all patients and at all dose levels, the overall response rate was 24% in the second-line setting, 20% in the third-line setting, 28% for those sensitive to first-line combination chemotherapy, and 16% for those refractory or resistant to chemotherapy, Dr. Pietanza reported.
For the DLL3-positive patients in the expansion cohorts, the overall response rate reached 64% for those sensitive to first-line chemotherapy, 44% in the second-line setting, 45% in the third-line setting, and 23% for those refractory or resistant to chemotherapy.
Importantly, responses were durable, Dr. Pietanza observed. At the 0.3 mg/kg 6-week dosing schedule, patients had ongoing responses 189 days after confirmatory CT scans and survival remains prolonged. For these reasons, the dose of 0.3 mg/kg every 6 weeks was chosen as the randomized phase II dose, she added.
Dr. Pietanza highlighted the benefits of rovalpituzumab tesirine by describing one patient who had a partial response to the first dose that continued, with a 51% reduction in tumor volume and a negative PET scan at 120 days. An adrenalectomy was performed at about 220 days due to ongoing response and disease presence only in the adrenal gland.
“Upon pathology review, there was a 95% treatment effect on the tumor,” she said. “When the adrenal gland was stained for Ki67, which is a marker of proliferative index, it was completely negative, noting and underscoring that possibly Rova-T affects tumor initiating cells.
“My patient remains alive with no evidence of disease over 1 year after first administration of Rova-T.”
The drug has a manageable safety profile, with unique reactions being pleural effusions and photosensitivity, she said.
Among 69 evaluable patients in the dose-escalation cohorts, the most common treatment-related adverse events of any grade were fatigue (28%), peripheral edema (17%), maculopapular rash (14%), thrombocytopenia (14%), pleural effusion (13%), and photosensitivity (12%), Dr. Pietanza said.
The most frequent grade 3/4 events were thrombocytopenia (9%), fatigue (6%), maculopapular rash (4%), and pleural effusion (4%).
“These results support biomarker-guided phase II studies,” she concluded.
Discussant Dr. Martin Reck, of the Lung Clinic Grosshansdorf (Germany), said, “We have seen very interesting results, perhaps the first targeted treatment in small-cell lung cancer. The data are very much superior to topotecan.”
More clinical data are needed, however, and the results must be put into perspective with the immunotherapies, where encouraging results have also been seen in SCLC, he said. The optimal treatment setting also has to be determined for rovalpituzumab tesirine, whether it is maintenance or perhaps a combination strategy.
Professor Peter Naredi, scientific cochair of the congress, said in a statement that the early results are “remarkable” in a malignancy where there has been no novel treatment options for years.
On Twitter @pwendl
VIENNA – Rovalpituzumab tesirine, an antibody drug conjugate that targets delta-like protein 3, produced responses in a range of patients with previously treated small-cell lung cancer in a phase I study.
Responses to rovalpituzumab tesirine (Rova-T) were higher and more durable in patients with tumors positive for DLL3, a protein previously shown to be over-expressed in about 70% of small-cell lung cancers (SCLCs).
“DLL3 may be the first predictive biomarker associated with treatment efficacy in small-cell lung cancer,” Dr. M. Catherine Pietanza of Memorial Sloan Kettering Cancer Center, New York City, said during a presidential session at the European Cancer Congress 2015.
While SCLC is initially sensitive to chemotherapy and radiation, resistance develops quickly. Topotecan (Hycamtin) is the only approved agent in the second-line setting. None are available in the third-line setting and outcomes remain dismal, with 5-year survival rates of 6%, she said.
The study enrolled 73 patients with recurrent or progressive SCLC after first- or second-line therapy and administered escalating doses of rovalpituzumab tesirine (0.05 mg/kg to 0.8 mg/kg) once every 3 weeks. Confirmed responses were observed at the 0.2-mg/kg, 0.3-mg/kg, and 0.4-mg/kg dose levels.
The maximum tolerated dose was 0.4 mg/kg, but continued dosing revealed cumulative toxicities, most often serosal effusions, Dr. Pietanza said. The agent was also found to have a prolonged half-life, prompting the researchers to proceed with rovalpituzumab tesirine 0.2 mg/kg every 3 weeks and 0.3 mg/kg every 6 weeks in the phase Ib expansion cohorts.
The patients median age was 61 years and 56% were male. Of the 49 tumor samples available for analysis, 71% were positive for high DLL3 expression using an H score cutoff of at least 180 on a scale of 300.
For all patients and at all dose levels, the overall response rate was 24% in the second-line setting, 20% in the third-line setting, 28% for those sensitive to first-line combination chemotherapy, and 16% for those refractory or resistant to chemotherapy, Dr. Pietanza reported.
For the DLL3-positive patients in the expansion cohorts, the overall response rate reached 64% for those sensitive to first-line chemotherapy, 44% in the second-line setting, 45% in the third-line setting, and 23% for those refractory or resistant to chemotherapy.
Importantly, responses were durable, Dr. Pietanza observed. At the 0.3 mg/kg 6-week dosing schedule, patients had ongoing responses 189 days after confirmatory CT scans and survival remains prolonged. For these reasons, the dose of 0.3 mg/kg every 6 weeks was chosen as the randomized phase II dose, she added.
Dr. Pietanza highlighted the benefits of rovalpituzumab tesirine by describing one patient who had a partial response to the first dose that continued, with a 51% reduction in tumor volume and a negative PET scan at 120 days. An adrenalectomy was performed at about 220 days due to ongoing response and disease presence only in the adrenal gland.
“Upon pathology review, there was a 95% treatment effect on the tumor,” she said. “When the adrenal gland was stained for Ki67, which is a marker of proliferative index, it was completely negative, noting and underscoring that possibly Rova-T affects tumor initiating cells.
“My patient remains alive with no evidence of disease over 1 year after first administration of Rova-T.”
The drug has a manageable safety profile, with unique reactions being pleural effusions and photosensitivity, she said.
Among 69 evaluable patients in the dose-escalation cohorts, the most common treatment-related adverse events of any grade were fatigue (28%), peripheral edema (17%), maculopapular rash (14%), thrombocytopenia (14%), pleural effusion (13%), and photosensitivity (12%), Dr. Pietanza said.
The most frequent grade 3/4 events were thrombocytopenia (9%), fatigue (6%), maculopapular rash (4%), and pleural effusion (4%).
“These results support biomarker-guided phase II studies,” she concluded.
Discussant Dr. Martin Reck, of the Lung Clinic Grosshansdorf (Germany), said, “We have seen very interesting results, perhaps the first targeted treatment in small-cell lung cancer. The data are very much superior to topotecan.”
More clinical data are needed, however, and the results must be put into perspective with the immunotherapies, where encouraging results have also been seen in SCLC, he said. The optimal treatment setting also has to be determined for rovalpituzumab tesirine, whether it is maintenance or perhaps a combination strategy.
Professor Peter Naredi, scientific cochair of the congress, said in a statement that the early results are “remarkable” in a malignancy where there has been no novel treatment options for years.
On Twitter @pwendl
VIENNA – Rovalpituzumab tesirine, an antibody drug conjugate that targets delta-like protein 3, produced responses in a range of patients with previously treated small-cell lung cancer in a phase I study.
Responses to rovalpituzumab tesirine (Rova-T) were higher and more durable in patients with tumors positive for DLL3, a protein previously shown to be over-expressed in about 70% of small-cell lung cancers (SCLCs).
“DLL3 may be the first predictive biomarker associated with treatment efficacy in small-cell lung cancer,” Dr. M. Catherine Pietanza of Memorial Sloan Kettering Cancer Center, New York City, said during a presidential session at the European Cancer Congress 2015.
While SCLC is initially sensitive to chemotherapy and radiation, resistance develops quickly. Topotecan (Hycamtin) is the only approved agent in the second-line setting. None are available in the third-line setting and outcomes remain dismal, with 5-year survival rates of 6%, she said.
The study enrolled 73 patients with recurrent or progressive SCLC after first- or second-line therapy and administered escalating doses of rovalpituzumab tesirine (0.05 mg/kg to 0.8 mg/kg) once every 3 weeks. Confirmed responses were observed at the 0.2-mg/kg, 0.3-mg/kg, and 0.4-mg/kg dose levels.
The maximum tolerated dose was 0.4 mg/kg, but continued dosing revealed cumulative toxicities, most often serosal effusions, Dr. Pietanza said. The agent was also found to have a prolonged half-life, prompting the researchers to proceed with rovalpituzumab tesirine 0.2 mg/kg every 3 weeks and 0.3 mg/kg every 6 weeks in the phase Ib expansion cohorts.
The patients median age was 61 years and 56% were male. Of the 49 tumor samples available for analysis, 71% were positive for high DLL3 expression using an H score cutoff of at least 180 on a scale of 300.
For all patients and at all dose levels, the overall response rate was 24% in the second-line setting, 20% in the third-line setting, 28% for those sensitive to first-line combination chemotherapy, and 16% for those refractory or resistant to chemotherapy, Dr. Pietanza reported.
For the DLL3-positive patients in the expansion cohorts, the overall response rate reached 64% for those sensitive to first-line chemotherapy, 44% in the second-line setting, 45% in the third-line setting, and 23% for those refractory or resistant to chemotherapy.
Importantly, responses were durable, Dr. Pietanza observed. At the 0.3 mg/kg 6-week dosing schedule, patients had ongoing responses 189 days after confirmatory CT scans and survival remains prolonged. For these reasons, the dose of 0.3 mg/kg every 6 weeks was chosen as the randomized phase II dose, she added.
Dr. Pietanza highlighted the benefits of rovalpituzumab tesirine by describing one patient who had a partial response to the first dose that continued, with a 51% reduction in tumor volume and a negative PET scan at 120 days. An adrenalectomy was performed at about 220 days due to ongoing response and disease presence only in the adrenal gland.
“Upon pathology review, there was a 95% treatment effect on the tumor,” she said. “When the adrenal gland was stained for Ki67, which is a marker of proliferative index, it was completely negative, noting and underscoring that possibly Rova-T affects tumor initiating cells.
“My patient remains alive with no evidence of disease over 1 year after first administration of Rova-T.”
The drug has a manageable safety profile, with unique reactions being pleural effusions and photosensitivity, she said.
Among 69 evaluable patients in the dose-escalation cohorts, the most common treatment-related adverse events of any grade were fatigue (28%), peripheral edema (17%), maculopapular rash (14%), thrombocytopenia (14%), pleural effusion (13%), and photosensitivity (12%), Dr. Pietanza said.
The most frequent grade 3/4 events were thrombocytopenia (9%), fatigue (6%), maculopapular rash (4%), and pleural effusion (4%).
“These results support biomarker-guided phase II studies,” she concluded.
Discussant Dr. Martin Reck, of the Lung Clinic Grosshansdorf (Germany), said, “We have seen very interesting results, perhaps the first targeted treatment in small-cell lung cancer. The data are very much superior to topotecan.”
More clinical data are needed, however, and the results must be put into perspective with the immunotherapies, where encouraging results have also been seen in SCLC, he said. The optimal treatment setting also has to be determined for rovalpituzumab tesirine, whether it is maintenance or perhaps a combination strategy.
Professor Peter Naredi, scientific cochair of the congress, said in a statement that the early results are “remarkable” in a malignancy where there has been no novel treatment options for years.
On Twitter @pwendl
AT EUROPEAN CANCER CONGRESS 2015
Key clinical point: Rovalpituzumab tesirine has single-agent activity in small-cell lung cancer, a malignancy with high unmet need.
Major finding: Among all patients, the overall response rate was 24% in the second-line setting and 20% in the third-line setting.
Data source: Phase I study of 73 patients with pretreated recurrent or progressive small-cell lung cancer.
Disclosures: Stemcentrx sponsored the trial. Dr Pietanza reported paid consultancy for Celgene, Clovis Oncology, and AbbVie.
Sleeve gastrectomy cut biochemical cardiac risk factors
CHICAGO – Many traditional and novel biochemical cardiac risk markers show dramatic and stable improvements following sleeve gastrectomy, a prospective, observational study shows.
C-reactive protein (CRP) levels were elevated in 78% of patients preoperatively, but they fell early in the preoperative course at 3 months (median 6.6 mg/L vs. 4.5 mg/L; P less than .0001) and continued to decline throughout the 12-month follow-up (median 5.8 mg/L vs. 2.4 mg/L; P less than .0001).
“This gradual improvement and normalization of this inflammatory marker may reflect the slower resolution of the chronic inflammatory burden that obesity brings along with it,” Ms. Tara Mokhtari said at the American College of Surgeons Clinical Congress.
Though prior studies have shown that gastric bypass and adjustable gastric banding improved biochemical cardiac risk factors (BCRFs), this is the first prospective study to detail such improvements following sleeve gastrectomy.
The study evaluated 10 BCRFs (total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides (TG), TC/HDL ratio, hemoglobin A1c, TG/HDL ratio, homocysteine, lipoprotein A, and CRP) in 334 morbidly obese patients undergoing laparoscopic sleeve gastrectomy during 2006-2015. Their mean age was 45 years, 76.4% were women, 55% were hypertensive, 29.4% had diabetes, 9.6% had known coronary artery disease, and 26.4% were on a lipid-lowering medication.
Many patients had abnormal cardiac risk factors prior to surgery, the most striking being the 78% of patients with elevated CRP levels (at least 3 mg/L), according to Ms. Mokhtari of Stanford (Calif.) University.
One-third also had abnormal HDL levels, total cholesterol, and triglyceride/HDL ratio and 20% had LDL levels above the 130 mg/dL threshold. Statin use was discontinued in all patients following surgery, per hospital protocol.
After sleeve gastrectomy, body mass index declined from 43.5 preoperatively to 36.6 at 3 months, 34.3 at 6 months, and 33.1 at 12 months, according to the study authors, led by Dr. John M. Morton, also of Stanford.
Similar to the early changes observed in CRP, there were significant changes from baseline at 3 months in triglycerides (116.5 mg/dL vs. 98.5 mg/dL; P less than .0001) and HbA1c (5.8% vs. 5.5%; P less than .0001).
Six months after sleeve gastrectomy, significant improvements were seen in these same risk factors as well as HDL cholesterol (47 mg/dL vs. 51 mg/dL; P less than .0001), TG/HDL ratio, a surrogate marker for metabolic syndrome (2.5 vs. 1.9; P less than .0001), and lipoprotein A (8.9 mg/dL vs. 5.4 mg/dL; P = .016), Ms. Mokhtari said.
By 12 months, all cardiac risk factors except LDL cholesterol (median preop 101.5 mg/dL vs. 102.5 mg/dL; P = .062) were significantly improved. Notably, HDL increased to a median of 54 mg/dL, triglycerides continued to decline to 93 mg/dL, and HgA1c held steady at 5.5%.
“Triglycerides fell dramatically and remained stable, which in combination with the increase in HDL, reflects a much healthier overall lipid profile for our post-sleeve patients,” Ms. Mokhtari said. “It’s important to recall that all of these improvements were seen without the use of a statin drug.”
Improvement in these cardiac biomarkers may further represent improvements in other obesity-related diseases, as evidenced by improvements in the markers for type II diabetes and metabolic syndrome, she said.
“Such risk factors are useful in determining baseline risk for our sleeve patients and also can be followed very easily in the postoperative period,” Ms. Mokhtari added.
Discussant Dr. Aurora D. Pryor of State University of New York at Stony Brook, congratulated the authors on their research and asked how sleeve gastrectomy stacks up to gastric bypass or banding as a procedure for metabolic disease and whether the biomarker improvements will translate into improved mortality.
There are several published reports on cardiac risk factors and gastric banding and Roux-en-Y gastric bypass, but many do not include the newer biomarkers of lipoprotein A, homocysteine, or CRP, Ms. Mokhtari observed. A 2006 study by the Stanford investigators, however, suggests that “overall, Roux-en-Y allowed for a more significant improvement in these risk factors compared to sleeve,” she said.
Ms. Mokhtari went on to say that the SOS study reported a decrease in cardiovascular events after Roux-en-Y bypass, but that no such solid evidence exists for sleeve gastrectomy. However, studies have shown comparable improvements in Framingham risk scores at 1 year between sleeve and Roux-en-Y.
CHICAGO – Many traditional and novel biochemical cardiac risk markers show dramatic and stable improvements following sleeve gastrectomy, a prospective, observational study shows.
C-reactive protein (CRP) levels were elevated in 78% of patients preoperatively, but they fell early in the preoperative course at 3 months (median 6.6 mg/L vs. 4.5 mg/L; P less than .0001) and continued to decline throughout the 12-month follow-up (median 5.8 mg/L vs. 2.4 mg/L; P less than .0001).
“This gradual improvement and normalization of this inflammatory marker may reflect the slower resolution of the chronic inflammatory burden that obesity brings along with it,” Ms. Tara Mokhtari said at the American College of Surgeons Clinical Congress.
Though prior studies have shown that gastric bypass and adjustable gastric banding improved biochemical cardiac risk factors (BCRFs), this is the first prospective study to detail such improvements following sleeve gastrectomy.
The study evaluated 10 BCRFs (total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides (TG), TC/HDL ratio, hemoglobin A1c, TG/HDL ratio, homocysteine, lipoprotein A, and CRP) in 334 morbidly obese patients undergoing laparoscopic sleeve gastrectomy during 2006-2015. Their mean age was 45 years, 76.4% were women, 55% were hypertensive, 29.4% had diabetes, 9.6% had known coronary artery disease, and 26.4% were on a lipid-lowering medication.
Many patients had abnormal cardiac risk factors prior to surgery, the most striking being the 78% of patients with elevated CRP levels (at least 3 mg/L), according to Ms. Mokhtari of Stanford (Calif.) University.
One-third also had abnormal HDL levels, total cholesterol, and triglyceride/HDL ratio and 20% had LDL levels above the 130 mg/dL threshold. Statin use was discontinued in all patients following surgery, per hospital protocol.
After sleeve gastrectomy, body mass index declined from 43.5 preoperatively to 36.6 at 3 months, 34.3 at 6 months, and 33.1 at 12 months, according to the study authors, led by Dr. John M. Morton, also of Stanford.
Similar to the early changes observed in CRP, there were significant changes from baseline at 3 months in triglycerides (116.5 mg/dL vs. 98.5 mg/dL; P less than .0001) and HbA1c (5.8% vs. 5.5%; P less than .0001).
Six months after sleeve gastrectomy, significant improvements were seen in these same risk factors as well as HDL cholesterol (47 mg/dL vs. 51 mg/dL; P less than .0001), TG/HDL ratio, a surrogate marker for metabolic syndrome (2.5 vs. 1.9; P less than .0001), and lipoprotein A (8.9 mg/dL vs. 5.4 mg/dL; P = .016), Ms. Mokhtari said.
By 12 months, all cardiac risk factors except LDL cholesterol (median preop 101.5 mg/dL vs. 102.5 mg/dL; P = .062) were significantly improved. Notably, HDL increased to a median of 54 mg/dL, triglycerides continued to decline to 93 mg/dL, and HgA1c held steady at 5.5%.
“Triglycerides fell dramatically and remained stable, which in combination with the increase in HDL, reflects a much healthier overall lipid profile for our post-sleeve patients,” Ms. Mokhtari said. “It’s important to recall that all of these improvements were seen without the use of a statin drug.”
Improvement in these cardiac biomarkers may further represent improvements in other obesity-related diseases, as evidenced by improvements in the markers for type II diabetes and metabolic syndrome, she said.
“Such risk factors are useful in determining baseline risk for our sleeve patients and also can be followed very easily in the postoperative period,” Ms. Mokhtari added.
Discussant Dr. Aurora D. Pryor of State University of New York at Stony Brook, congratulated the authors on their research and asked how sleeve gastrectomy stacks up to gastric bypass or banding as a procedure for metabolic disease and whether the biomarker improvements will translate into improved mortality.
There are several published reports on cardiac risk factors and gastric banding and Roux-en-Y gastric bypass, but many do not include the newer biomarkers of lipoprotein A, homocysteine, or CRP, Ms. Mokhtari observed. A 2006 study by the Stanford investigators, however, suggests that “overall, Roux-en-Y allowed for a more significant improvement in these risk factors compared to sleeve,” she said.
Ms. Mokhtari went on to say that the SOS study reported a decrease in cardiovascular events after Roux-en-Y bypass, but that no such solid evidence exists for sleeve gastrectomy. However, studies have shown comparable improvements in Framingham risk scores at 1 year between sleeve and Roux-en-Y.
CHICAGO – Many traditional and novel biochemical cardiac risk markers show dramatic and stable improvements following sleeve gastrectomy, a prospective, observational study shows.
C-reactive protein (CRP) levels were elevated in 78% of patients preoperatively, but they fell early in the preoperative course at 3 months (median 6.6 mg/L vs. 4.5 mg/L; P less than .0001) and continued to decline throughout the 12-month follow-up (median 5.8 mg/L vs. 2.4 mg/L; P less than .0001).
“This gradual improvement and normalization of this inflammatory marker may reflect the slower resolution of the chronic inflammatory burden that obesity brings along with it,” Ms. Tara Mokhtari said at the American College of Surgeons Clinical Congress.
Though prior studies have shown that gastric bypass and adjustable gastric banding improved biochemical cardiac risk factors (BCRFs), this is the first prospective study to detail such improvements following sleeve gastrectomy.
The study evaluated 10 BCRFs (total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides (TG), TC/HDL ratio, hemoglobin A1c, TG/HDL ratio, homocysteine, lipoprotein A, and CRP) in 334 morbidly obese patients undergoing laparoscopic sleeve gastrectomy during 2006-2015. Their mean age was 45 years, 76.4% were women, 55% were hypertensive, 29.4% had diabetes, 9.6% had known coronary artery disease, and 26.4% were on a lipid-lowering medication.
Many patients had abnormal cardiac risk factors prior to surgery, the most striking being the 78% of patients with elevated CRP levels (at least 3 mg/L), according to Ms. Mokhtari of Stanford (Calif.) University.
One-third also had abnormal HDL levels, total cholesterol, and triglyceride/HDL ratio and 20% had LDL levels above the 130 mg/dL threshold. Statin use was discontinued in all patients following surgery, per hospital protocol.
After sleeve gastrectomy, body mass index declined from 43.5 preoperatively to 36.6 at 3 months, 34.3 at 6 months, and 33.1 at 12 months, according to the study authors, led by Dr. John M. Morton, also of Stanford.
Similar to the early changes observed in CRP, there were significant changes from baseline at 3 months in triglycerides (116.5 mg/dL vs. 98.5 mg/dL; P less than .0001) and HbA1c (5.8% vs. 5.5%; P less than .0001).
Six months after sleeve gastrectomy, significant improvements were seen in these same risk factors as well as HDL cholesterol (47 mg/dL vs. 51 mg/dL; P less than .0001), TG/HDL ratio, a surrogate marker for metabolic syndrome (2.5 vs. 1.9; P less than .0001), and lipoprotein A (8.9 mg/dL vs. 5.4 mg/dL; P = .016), Ms. Mokhtari said.
By 12 months, all cardiac risk factors except LDL cholesterol (median preop 101.5 mg/dL vs. 102.5 mg/dL; P = .062) were significantly improved. Notably, HDL increased to a median of 54 mg/dL, triglycerides continued to decline to 93 mg/dL, and HgA1c held steady at 5.5%.
“Triglycerides fell dramatically and remained stable, which in combination with the increase in HDL, reflects a much healthier overall lipid profile for our post-sleeve patients,” Ms. Mokhtari said. “It’s important to recall that all of these improvements were seen without the use of a statin drug.”
Improvement in these cardiac biomarkers may further represent improvements in other obesity-related diseases, as evidenced by improvements in the markers for type II diabetes and metabolic syndrome, she said.
“Such risk factors are useful in determining baseline risk for our sleeve patients and also can be followed very easily in the postoperative period,” Ms. Mokhtari added.
Discussant Dr. Aurora D. Pryor of State University of New York at Stony Brook, congratulated the authors on their research and asked how sleeve gastrectomy stacks up to gastric bypass or banding as a procedure for metabolic disease and whether the biomarker improvements will translate into improved mortality.
There are several published reports on cardiac risk factors and gastric banding and Roux-en-Y gastric bypass, but many do not include the newer biomarkers of lipoprotein A, homocysteine, or CRP, Ms. Mokhtari observed. A 2006 study by the Stanford investigators, however, suggests that “overall, Roux-en-Y allowed for a more significant improvement in these risk factors compared to sleeve,” she said.
Ms. Mokhtari went on to say that the SOS study reported a decrease in cardiovascular events after Roux-en-Y bypass, but that no such solid evidence exists for sleeve gastrectomy. However, studies have shown comparable improvements in Framingham risk scores at 1 year between sleeve and Roux-en-Y.
AT THE AMERICAN COLLEGE OF SURGEONS CLINICAL CONGRESS
Key clinical point: Sleeve gastrectomy provided 12-month improvements in biochemical cardiovascular risk factors as well as weight and diabetes.
Major finding: CRP showed significant improvement within 3 months (median, 6.6 mg/L vs. 4.5 mg/L; P less than .0001).
Data source: Prospective, observational study in 334 morbidly obese patients undergoing sleeve gastrectomy.
Disclosures: Dr. Morton reported serving as a consultant for Ethicon and Medtronic.
VIDEO: Dialysis-dependent patients face rocky road after colorectal surgery
CHICAGO – The odds of emergency surgery were sevenfold higher in dialysis-dependent patients undergoing colorectal surgery than patients with renal insufficiency not on dialysis or those with normal renal function.
Dialysis patients were also far less likely to undergo laparoscopic surgery and to be rescued from death if they experienced a complication.
These are just some of the results of a retrospective study involving 156,645 elective colorectal surgery cases selected as a poster of exceptional merit here at the annual clinical congress of the American College of Surgeons.
Dialysis patients are known to be at high risk for postoperative complications, but few studies have evaluated outcomes after colorectal surgery in these patients or distinguished them from patients with non–dialysis dependent renal insufficiency (NDDRI) or normal renal function (NRF), observed study author Dr. Isibor Arhuidese of Johns Hopkins University in Baltimore.
Indeed, when the researchers compared these three groups, perioperative mortality and morbidity after elective colorectal surgery was the worst in dialysis patients.
Absolute perioperative mortality was highest for dialysis patients vs. NDDRI and NRF patients after open (13.4% vs. 4.8% vs. 2%; P less than .001) and laparoscopic (8% vs. 2% vs. 0.6%; P less than .001) surgery.
Three complications were significantly associated with death in dialysis patients: myocardial infarction (adjusted odds ratio, 48.6; P = .027), bleeding (aOR, 14.5; P = .025), and sepsis or septic shock (aOR, 8.7; P = .001).
It is not enough to simply identify dialysis dependence as a predictor of poor outcomes, but one must identify targets for improvement in surgical care, Dr. Arhuidese stressed.
Dr. Arhuidese reported having no relevant conflicts of interest.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
CHICAGO – The odds of emergency surgery were sevenfold higher in dialysis-dependent patients undergoing colorectal surgery than patients with renal insufficiency not on dialysis or those with normal renal function.
Dialysis patients were also far less likely to undergo laparoscopic surgery and to be rescued from death if they experienced a complication.
These are just some of the results of a retrospective study involving 156,645 elective colorectal surgery cases selected as a poster of exceptional merit here at the annual clinical congress of the American College of Surgeons.
Dialysis patients are known to be at high risk for postoperative complications, but few studies have evaluated outcomes after colorectal surgery in these patients or distinguished them from patients with non–dialysis dependent renal insufficiency (NDDRI) or normal renal function (NRF), observed study author Dr. Isibor Arhuidese of Johns Hopkins University in Baltimore.
Indeed, when the researchers compared these three groups, perioperative mortality and morbidity after elective colorectal surgery was the worst in dialysis patients.
Absolute perioperative mortality was highest for dialysis patients vs. NDDRI and NRF patients after open (13.4% vs. 4.8% vs. 2%; P less than .001) and laparoscopic (8% vs. 2% vs. 0.6%; P less than .001) surgery.
Three complications were significantly associated with death in dialysis patients: myocardial infarction (adjusted odds ratio, 48.6; P = .027), bleeding (aOR, 14.5; P = .025), and sepsis or septic shock (aOR, 8.7; P = .001).
It is not enough to simply identify dialysis dependence as a predictor of poor outcomes, but one must identify targets for improvement in surgical care, Dr. Arhuidese stressed.
Dr. Arhuidese reported having no relevant conflicts of interest.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
CHICAGO – The odds of emergency surgery were sevenfold higher in dialysis-dependent patients undergoing colorectal surgery than patients with renal insufficiency not on dialysis or those with normal renal function.
Dialysis patients were also far less likely to undergo laparoscopic surgery and to be rescued from death if they experienced a complication.
These are just some of the results of a retrospective study involving 156,645 elective colorectal surgery cases selected as a poster of exceptional merit here at the annual clinical congress of the American College of Surgeons.
Dialysis patients are known to be at high risk for postoperative complications, but few studies have evaluated outcomes after colorectal surgery in these patients or distinguished them from patients with non–dialysis dependent renal insufficiency (NDDRI) or normal renal function (NRF), observed study author Dr. Isibor Arhuidese of Johns Hopkins University in Baltimore.
Indeed, when the researchers compared these three groups, perioperative mortality and morbidity after elective colorectal surgery was the worst in dialysis patients.
Absolute perioperative mortality was highest for dialysis patients vs. NDDRI and NRF patients after open (13.4% vs. 4.8% vs. 2%; P less than .001) and laparoscopic (8% vs. 2% vs. 0.6%; P less than .001) surgery.
Three complications were significantly associated with death in dialysis patients: myocardial infarction (adjusted odds ratio, 48.6; P = .027), bleeding (aOR, 14.5; P = .025), and sepsis or septic shock (aOR, 8.7; P = .001).
It is not enough to simply identify dialysis dependence as a predictor of poor outcomes, but one must identify targets for improvement in surgical care, Dr. Arhuidese stressed.
Dr. Arhuidese reported having no relevant conflicts of interest.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
AT THE ACS CLINICAL CONGRESS
Everolimus makes splash in lung, GI neuroendocrine tumors
VIENNA – The mTOR inhibitor everolimus cut the risk of progression or death by 52% for patients with advanced, progressive, nonfunctional lung or gastrointestinal neuroendocrine tumors in RADIANT-4.
Median progression-free survival (PFS) by central review was 11.0 months with everolimus vs. 3.9 months with placebo (hazard ratio, 0.48; P less than .00001).
The robust benefit was confirmed in investigator assessment (median PFS, 14.0 months vs. 5.5 months; HR, 0.39; P less than .00001).
“Everolimus is the first targeted agent to show robust antitumor activity with acceptable toxicity across a broad spectrum of neuroendocrine tumors, including those arising from the pancreas, lung, and gastrointestinal tract,” Dr. James Yao, chair of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center, Houston, said in a presidential session at the European Society for Medical Oncology congress.
The resultsare particularly important for patients with lung neuroendocrine tumors (NETs) because there is currently no approved treatment for such cases.
Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is already an approved standard of care in pancreatic NETs, based on the results of RADIANT-3.
Discussant Dr. Enrique Grande of Ram<scaps>ó</scaps>n y Cajal University Hospital in Madrid, said, “RADIANT-1, -2, -3, and now -4 results are all consistent and support the use of everolimus in grade 1 and 2 disseminated and progressive neuroendocrine regardless of primary tumor origin.”
That said, he observed that the median 11-month progression-free survival with everolimus is not superior to the 14.3-month PFS offered by the somatostatin analogue octreotide LAR in midgut NETs in PROMID, the 16.4-month PFS with everolimus plus octreotide LAR in RADIANT-2 in a cohort that included 15% lung NETs, or the 16.6-month PFS with bevacizumab (Avastin) plus octreotide LAR in a mixed cohort of NETs in SWOG S0518.
“Despite the encouraging activity favoring everolimus, we do not have the full picture yet,” Dr. Grande said. “Should everolimus be pushed after somatostatin analogue failure? If so, and this is something that most of the people here are doing, is single-agent everolimus better than maintenance of somatostatin analogues plus adding on everolimus?
“This is not like other tumor types, in which we are talking about first-line, second-line, third-line. We don’t have these things here. We have an unknown line of treatment.”
RADIANT-4 enrolled 302 patients with a median age of 63 years and randomized them in 2:1 ratio to everolimus 10 mg/day until disease progression or intolerable toxicity or to placebo. Patients were stratified by prior somatostatin analogue (SSA) treatment (yes vs. no), tumor origin (stratum A vs. stratum B), and WHO performance status (0 vs. 1). Stratum A (better prognosis) comprised appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary, while stratum B (worse prognosis) comprised lung, stomach, rectum, and colon except caecum. Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary analysis.
The most common primary tumor sites were lung and ileum in both the everolimus (31% and 23%) and placebo (28% and 25%) groups. In the everolimus group, 53% had prior SSA therapy, 59% surgery, 26% chemotherapy, and 22% radiotherapy. In the placebo group, the percentages were 56%, 72%, 24%, and 20%.
Overall, 64% of patients receiving everolimus had some tumor shrinkage vs. 26% receiving placebo, Dr. Yao said. The overall response rate, including complete and partial responses, was 2% vs. 1%. The disease control rate, which also included stable disease, was 82.4% vs. 65%.
The median duration of treatment was 40.4 weeks with everolimus and 19.6 weeks with placebo.
A consistent PFS benefit was seen with everolimus regardless of stratification factors, age, sex, race, tumor grade, prior therapy, and baseline chromogranin A or neuron-specific enolase status, he said.
Benefits also were seen across hepatic tumor load. This included an 82% reduction in progression with everolimus (HR, 0.18) among those with heavy liver tumor burden (greater than 25%), “a group of patients that really needs treatment,” Dr. Yao said.
The PFS benefit also was consistent across primary tumor site: lung (HR, 0.50), GI (HR, 0.56), and NET of unknown primary (HR, 0.60).
The first interim overall analysis showed a 36% reduction in the risk of death with everolimus (HR, 0.64; P = .037), but this was not statistically significant based on the prespecified P value boundary for significance of 0.0002, Dr. Yao said. There were 41 deaths in the everolimus arm and 28 in the placebo arm, of which 3.5% vs. 3.1% were on-treatment deaths. The next interim analysis is expected in 2016.
The safety profile was consistent with the known profile of everolimus, he said. In the everolimus arm, the most common drug-related adverse events of any grade were stomatitis (63%), diarrhea (31%), fatigue (31%), and infections (29%). Common grade 3/4 events were stomatitis (9%), diarrhea (7%), infections (7%), and fatigue (3%).
Dr. Peter Naredi, scientific cochair of the congress, commented that this year’s meeting is particularly exciting for clinicians treating patients with neuroendocrine tumors because two trials, RADIANT-4 and NETTER-1 both show positive results.
On Twitter @pwendl
VIENNA – The mTOR inhibitor everolimus cut the risk of progression or death by 52% for patients with advanced, progressive, nonfunctional lung or gastrointestinal neuroendocrine tumors in RADIANT-4.
Median progression-free survival (PFS) by central review was 11.0 months with everolimus vs. 3.9 months with placebo (hazard ratio, 0.48; P less than .00001).
The robust benefit was confirmed in investigator assessment (median PFS, 14.0 months vs. 5.5 months; HR, 0.39; P less than .00001).
“Everolimus is the first targeted agent to show robust antitumor activity with acceptable toxicity across a broad spectrum of neuroendocrine tumors, including those arising from the pancreas, lung, and gastrointestinal tract,” Dr. James Yao, chair of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center, Houston, said in a presidential session at the European Society for Medical Oncology congress.
The resultsare particularly important for patients with lung neuroendocrine tumors (NETs) because there is currently no approved treatment for such cases.
Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is already an approved standard of care in pancreatic NETs, based on the results of RADIANT-3.
Discussant Dr. Enrique Grande of Ram<scaps>ó</scaps>n y Cajal University Hospital in Madrid, said, “RADIANT-1, -2, -3, and now -4 results are all consistent and support the use of everolimus in grade 1 and 2 disseminated and progressive neuroendocrine regardless of primary tumor origin.”
That said, he observed that the median 11-month progression-free survival with everolimus is not superior to the 14.3-month PFS offered by the somatostatin analogue octreotide LAR in midgut NETs in PROMID, the 16.4-month PFS with everolimus plus octreotide LAR in RADIANT-2 in a cohort that included 15% lung NETs, or the 16.6-month PFS with bevacizumab (Avastin) plus octreotide LAR in a mixed cohort of NETs in SWOG S0518.
“Despite the encouraging activity favoring everolimus, we do not have the full picture yet,” Dr. Grande said. “Should everolimus be pushed after somatostatin analogue failure? If so, and this is something that most of the people here are doing, is single-agent everolimus better than maintenance of somatostatin analogues plus adding on everolimus?
“This is not like other tumor types, in which we are talking about first-line, second-line, third-line. We don’t have these things here. We have an unknown line of treatment.”
RADIANT-4 enrolled 302 patients with a median age of 63 years and randomized them in 2:1 ratio to everolimus 10 mg/day until disease progression or intolerable toxicity or to placebo. Patients were stratified by prior somatostatin analogue (SSA) treatment (yes vs. no), tumor origin (stratum A vs. stratum B), and WHO performance status (0 vs. 1). Stratum A (better prognosis) comprised appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary, while stratum B (worse prognosis) comprised lung, stomach, rectum, and colon except caecum. Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary analysis.
The most common primary tumor sites were lung and ileum in both the everolimus (31% and 23%) and placebo (28% and 25%) groups. In the everolimus group, 53% had prior SSA therapy, 59% surgery, 26% chemotherapy, and 22% radiotherapy. In the placebo group, the percentages were 56%, 72%, 24%, and 20%.
Overall, 64% of patients receiving everolimus had some tumor shrinkage vs. 26% receiving placebo, Dr. Yao said. The overall response rate, including complete and partial responses, was 2% vs. 1%. The disease control rate, which also included stable disease, was 82.4% vs. 65%.
The median duration of treatment was 40.4 weeks with everolimus and 19.6 weeks with placebo.
A consistent PFS benefit was seen with everolimus regardless of stratification factors, age, sex, race, tumor grade, prior therapy, and baseline chromogranin A or neuron-specific enolase status, he said.
Benefits also were seen across hepatic tumor load. This included an 82% reduction in progression with everolimus (HR, 0.18) among those with heavy liver tumor burden (greater than 25%), “a group of patients that really needs treatment,” Dr. Yao said.
The PFS benefit also was consistent across primary tumor site: lung (HR, 0.50), GI (HR, 0.56), and NET of unknown primary (HR, 0.60).
The first interim overall analysis showed a 36% reduction in the risk of death with everolimus (HR, 0.64; P = .037), but this was not statistically significant based on the prespecified P value boundary for significance of 0.0002, Dr. Yao said. There were 41 deaths in the everolimus arm and 28 in the placebo arm, of which 3.5% vs. 3.1% were on-treatment deaths. The next interim analysis is expected in 2016.
The safety profile was consistent with the known profile of everolimus, he said. In the everolimus arm, the most common drug-related adverse events of any grade were stomatitis (63%), diarrhea (31%), fatigue (31%), and infections (29%). Common grade 3/4 events were stomatitis (9%), diarrhea (7%), infections (7%), and fatigue (3%).
Dr. Peter Naredi, scientific cochair of the congress, commented that this year’s meeting is particularly exciting for clinicians treating patients with neuroendocrine tumors because two trials, RADIANT-4 and NETTER-1 both show positive results.
On Twitter @pwendl
VIENNA – The mTOR inhibitor everolimus cut the risk of progression or death by 52% for patients with advanced, progressive, nonfunctional lung or gastrointestinal neuroendocrine tumors in RADIANT-4.
Median progression-free survival (PFS) by central review was 11.0 months with everolimus vs. 3.9 months with placebo (hazard ratio, 0.48; P less than .00001).
The robust benefit was confirmed in investigator assessment (median PFS, 14.0 months vs. 5.5 months; HR, 0.39; P less than .00001).
“Everolimus is the first targeted agent to show robust antitumor activity with acceptable toxicity across a broad spectrum of neuroendocrine tumors, including those arising from the pancreas, lung, and gastrointestinal tract,” Dr. James Yao, chair of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center, Houston, said in a presidential session at the European Society for Medical Oncology congress.
The resultsare particularly important for patients with lung neuroendocrine tumors (NETs) because there is currently no approved treatment for such cases.
Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is already an approved standard of care in pancreatic NETs, based on the results of RADIANT-3.
Discussant Dr. Enrique Grande of Ram<scaps>ó</scaps>n y Cajal University Hospital in Madrid, said, “RADIANT-1, -2, -3, and now -4 results are all consistent and support the use of everolimus in grade 1 and 2 disseminated and progressive neuroendocrine regardless of primary tumor origin.”
That said, he observed that the median 11-month progression-free survival with everolimus is not superior to the 14.3-month PFS offered by the somatostatin analogue octreotide LAR in midgut NETs in PROMID, the 16.4-month PFS with everolimus plus octreotide LAR in RADIANT-2 in a cohort that included 15% lung NETs, or the 16.6-month PFS with bevacizumab (Avastin) plus octreotide LAR in a mixed cohort of NETs in SWOG S0518.
“Despite the encouraging activity favoring everolimus, we do not have the full picture yet,” Dr. Grande said. “Should everolimus be pushed after somatostatin analogue failure? If so, and this is something that most of the people here are doing, is single-agent everolimus better than maintenance of somatostatin analogues plus adding on everolimus?
“This is not like other tumor types, in which we are talking about first-line, second-line, third-line. We don’t have these things here. We have an unknown line of treatment.”
RADIANT-4 enrolled 302 patients with a median age of 63 years and randomized them in 2:1 ratio to everolimus 10 mg/day until disease progression or intolerable toxicity or to placebo. Patients were stratified by prior somatostatin analogue (SSA) treatment (yes vs. no), tumor origin (stratum A vs. stratum B), and WHO performance status (0 vs. 1). Stratum A (better prognosis) comprised appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary, while stratum B (worse prognosis) comprised lung, stomach, rectum, and colon except caecum. Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary analysis.
The most common primary tumor sites were lung and ileum in both the everolimus (31% and 23%) and placebo (28% and 25%) groups. In the everolimus group, 53% had prior SSA therapy, 59% surgery, 26% chemotherapy, and 22% radiotherapy. In the placebo group, the percentages were 56%, 72%, 24%, and 20%.
Overall, 64% of patients receiving everolimus had some tumor shrinkage vs. 26% receiving placebo, Dr. Yao said. The overall response rate, including complete and partial responses, was 2% vs. 1%. The disease control rate, which also included stable disease, was 82.4% vs. 65%.
The median duration of treatment was 40.4 weeks with everolimus and 19.6 weeks with placebo.
A consistent PFS benefit was seen with everolimus regardless of stratification factors, age, sex, race, tumor grade, prior therapy, and baseline chromogranin A or neuron-specific enolase status, he said.
Benefits also were seen across hepatic tumor load. This included an 82% reduction in progression with everolimus (HR, 0.18) among those with heavy liver tumor burden (greater than 25%), “a group of patients that really needs treatment,” Dr. Yao said.
The PFS benefit also was consistent across primary tumor site: lung (HR, 0.50), GI (HR, 0.56), and NET of unknown primary (HR, 0.60).
The first interim overall analysis showed a 36% reduction in the risk of death with everolimus (HR, 0.64; P = .037), but this was not statistically significant based on the prespecified P value boundary for significance of 0.0002, Dr. Yao said. There were 41 deaths in the everolimus arm and 28 in the placebo arm, of which 3.5% vs. 3.1% were on-treatment deaths. The next interim analysis is expected in 2016.
The safety profile was consistent with the known profile of everolimus, he said. In the everolimus arm, the most common drug-related adverse events of any grade were stomatitis (63%), diarrhea (31%), fatigue (31%), and infections (29%). Common grade 3/4 events were stomatitis (9%), diarrhea (7%), infections (7%), and fatigue (3%).
Dr. Peter Naredi, scientific cochair of the congress, commented that this year’s meeting is particularly exciting for clinicians treating patients with neuroendocrine tumors because two trials, RADIANT-4 and NETTER-1 both show positive results.
On Twitter @pwendl
AT THE EUROPEAN CANCER CONGRESS 2015
Key clinical point: Everolimus significantly delays tumor growth in advanced lung and gastrointestinal neuroendocrine tumors.
Major finding: Median progression-free survival was 11 months for everolimus vs. 3.9 months for placebo (hazard ratio, 0.39; P < .00001).
Data source: Double-blind phase III study in 302 patients with advanced, progressive lung and GI neuroendocrine tumors.
Disclosures: Novartis sponsored the study. Dr. Yao reported serving as a consultant to and receiving research funding from Novartis.
Radiopeptide therapy sparks unheard of PFS in midgut neuroendocrine tumors
VIENNA – After posting unprecedented results in the phase III NETTER-1 trial, the experimental radiopeptide therapy 177Lu-Dotatate looks poised to become a new treatment option for patients with midgut neuroendocrine tumors that progress on somatostatin analogues.
Median progression-free survival was not reached in patients receiving 177Lu-Dotatate (Lutathera) plus the somatostatin octreotide LAR (Sandostatin), the current standard of care, and was 8.4 months in those given a double dose of octreotide LAR.
This resulted in a hazard ratio of 0.209 (P less than .0001) or almost an 80% reduction in the risk for disease progression or death, Dr. Philippe Ruszniewski of Beaujon Hospital in Clichy, France, said at the European Society for Medical Oncology Congress.
The experimental therapy also was superior to octreotide LAR in terms of objective response rate (19% vs. 3%; P less than .0004). This included one complete response and 18 partial responses to 177Lu-Dotatate vs. 3 partial responses to octreotide LAR alone.
Although few treatment options were up to now available for this rare cancer, “Lu-Dotatate appears as a major advance in these patients,” he said.
Invited discussant Dr. Enrique Grande of Ram<scaps>ó</scaps>n y Cajal University Hospital in Madrid, commented, “This is the most impressive cohort in terms of progression-free survival that we have seen in the neuroendocrine tumors … especially since the comparator arm is a really active one that we are doing in routine practice.”
177Lu-Dotatate belongs to a drug category called peptide receptor radionuclide therapy and is composed of a lutetium radionuclide chelated to a peptide. The 177Lutetium-labeled somatostatin analogue peptide targets somatostatin receptors, which are overexpressed in about 80% of neuroendocrine tumors (NETs).
177Lu-Dotatate has received orphan drug status from the Food and Drug Administration and the European Medicines Agency and in April 2015 also was granted fast-track designation by the FDA.
NETTER-1 enrolled 230 patients with metastatic or locally advanced, inoperable midgut NETs, functioning or not, and evenly randomized them to four doses of 7.4 GBq 177Lu-Dotatate intravenously over 8 weeks plus octreotide LAR 30 mg or to octreotide LAR 60 mg every 28 days given as a deep intragluteal injection. The ileum was the primary tumor site in three-fourths of patients and the liver the site of metastasis in about 83%.
Three-fourths of patients received all four doses of 177Lu-Dotatate and no dose-modifying toxicity was observed in 95% of all 111 treated patients, Dr. Ruszniewski said.
An interim analysis suggested increased overall survival (13 deaths vs. 22 deaths; P less than .018), but the data are immature and need to be confirmed by final analysis, he said.
Treatment-related adverse events of any grade were reported in 86% of patients given 177Lu-Dotatate and 31% on octreotide LAR 60 mg.
Treatment-related serious events occurred in 10 patients in the 177Lu-Dotatate arm vs. 1 in the octreotide arm, with withdrawals because of treatment-related adverse events in 5 vs. 0 patients, respectively.
Serious adverse events related to 177Lu-Dotatate included, but were not limited to, lymphocytopenia in seven patients, thrombocytopenia in three, acute kidney injury in two, and one case each of renal failure and portal hypertension.
When asked in a press briefing whether 177Lu-Dotatate could induce long-term DNA damage after hitting its target, Dr. Ruszniewski said a substudy in 20 unrelated patients will provide pharmacokinetic data on the fate of the radionuclide.
“What we know from phase I and II is that this is probably possible, but rare,” he said. “The two organs that should be carefully watched are the bone marrow and the kidneys.”
To reduce kidney damage, amino acids are infused at the same time as the radionuclide. Myelodysplastic syndrome might occur in 3% to 4% of patients, he added.
The investigators called for additional studies of 177Lu-Dotatate in other types of NETs such as pancreatic and bronchial.
When it was noted that the approved radioactive agent, radium-223 dichloride (Xofigo) also has very good data in pancreatic cancer but is often used behind other drugs because it is a radiopharmaceutical, Dr. Ruszniewski dismissed the suggestion and said NETs are a completely different disease.
Discussant Dr. Grande, however, said that there are logistical considerations surrounding 177-Lu-Dotatate, such as how clinicians would request it, whether it will be widely available, and where it would be delivered.
No special room is needed to treat patients with 177-Lu-Dotatate, but patient urine does have to be controlled, Dr. Ruszniewski noted.
On Twitter @pwendl
VIENNA – After posting unprecedented results in the phase III NETTER-1 trial, the experimental radiopeptide therapy 177Lu-Dotatate looks poised to become a new treatment option for patients with midgut neuroendocrine tumors that progress on somatostatin analogues.
Median progression-free survival was not reached in patients receiving 177Lu-Dotatate (Lutathera) plus the somatostatin octreotide LAR (Sandostatin), the current standard of care, and was 8.4 months in those given a double dose of octreotide LAR.
This resulted in a hazard ratio of 0.209 (P less than .0001) or almost an 80% reduction in the risk for disease progression or death, Dr. Philippe Ruszniewski of Beaujon Hospital in Clichy, France, said at the European Society for Medical Oncology Congress.
The experimental therapy also was superior to octreotide LAR in terms of objective response rate (19% vs. 3%; P less than .0004). This included one complete response and 18 partial responses to 177Lu-Dotatate vs. 3 partial responses to octreotide LAR alone.
Although few treatment options were up to now available for this rare cancer, “Lu-Dotatate appears as a major advance in these patients,” he said.
Invited discussant Dr. Enrique Grande of Ram<scaps>ó</scaps>n y Cajal University Hospital in Madrid, commented, “This is the most impressive cohort in terms of progression-free survival that we have seen in the neuroendocrine tumors … especially since the comparator arm is a really active one that we are doing in routine practice.”
177Lu-Dotatate belongs to a drug category called peptide receptor radionuclide therapy and is composed of a lutetium radionuclide chelated to a peptide. The 177Lutetium-labeled somatostatin analogue peptide targets somatostatin receptors, which are overexpressed in about 80% of neuroendocrine tumors (NETs).
177Lu-Dotatate has received orphan drug status from the Food and Drug Administration and the European Medicines Agency and in April 2015 also was granted fast-track designation by the FDA.
NETTER-1 enrolled 230 patients with metastatic or locally advanced, inoperable midgut NETs, functioning or not, and evenly randomized them to four doses of 7.4 GBq 177Lu-Dotatate intravenously over 8 weeks plus octreotide LAR 30 mg or to octreotide LAR 60 mg every 28 days given as a deep intragluteal injection. The ileum was the primary tumor site in three-fourths of patients and the liver the site of metastasis in about 83%.
Three-fourths of patients received all four doses of 177Lu-Dotatate and no dose-modifying toxicity was observed in 95% of all 111 treated patients, Dr. Ruszniewski said.
An interim analysis suggested increased overall survival (13 deaths vs. 22 deaths; P less than .018), but the data are immature and need to be confirmed by final analysis, he said.
Treatment-related adverse events of any grade were reported in 86% of patients given 177Lu-Dotatate and 31% on octreotide LAR 60 mg.
Treatment-related serious events occurred in 10 patients in the 177Lu-Dotatate arm vs. 1 in the octreotide arm, with withdrawals because of treatment-related adverse events in 5 vs. 0 patients, respectively.
Serious adverse events related to 177Lu-Dotatate included, but were not limited to, lymphocytopenia in seven patients, thrombocytopenia in three, acute kidney injury in two, and one case each of renal failure and portal hypertension.
When asked in a press briefing whether 177Lu-Dotatate could induce long-term DNA damage after hitting its target, Dr. Ruszniewski said a substudy in 20 unrelated patients will provide pharmacokinetic data on the fate of the radionuclide.
“What we know from phase I and II is that this is probably possible, but rare,” he said. “The two organs that should be carefully watched are the bone marrow and the kidneys.”
To reduce kidney damage, amino acids are infused at the same time as the radionuclide. Myelodysplastic syndrome might occur in 3% to 4% of patients, he added.
The investigators called for additional studies of 177Lu-Dotatate in other types of NETs such as pancreatic and bronchial.
When it was noted that the approved radioactive agent, radium-223 dichloride (Xofigo) also has very good data in pancreatic cancer but is often used behind other drugs because it is a radiopharmaceutical, Dr. Ruszniewski dismissed the suggestion and said NETs are a completely different disease.
Discussant Dr. Grande, however, said that there are logistical considerations surrounding 177-Lu-Dotatate, such as how clinicians would request it, whether it will be widely available, and where it would be delivered.
No special room is needed to treat patients with 177-Lu-Dotatate, but patient urine does have to be controlled, Dr. Ruszniewski noted.
On Twitter @pwendl
VIENNA – After posting unprecedented results in the phase III NETTER-1 trial, the experimental radiopeptide therapy 177Lu-Dotatate looks poised to become a new treatment option for patients with midgut neuroendocrine tumors that progress on somatostatin analogues.
Median progression-free survival was not reached in patients receiving 177Lu-Dotatate (Lutathera) plus the somatostatin octreotide LAR (Sandostatin), the current standard of care, and was 8.4 months in those given a double dose of octreotide LAR.
This resulted in a hazard ratio of 0.209 (P less than .0001) or almost an 80% reduction in the risk for disease progression or death, Dr. Philippe Ruszniewski of Beaujon Hospital in Clichy, France, said at the European Society for Medical Oncology Congress.
The experimental therapy also was superior to octreotide LAR in terms of objective response rate (19% vs. 3%; P less than .0004). This included one complete response and 18 partial responses to 177Lu-Dotatate vs. 3 partial responses to octreotide LAR alone.
Although few treatment options were up to now available for this rare cancer, “Lu-Dotatate appears as a major advance in these patients,” he said.
Invited discussant Dr. Enrique Grande of Ram<scaps>ó</scaps>n y Cajal University Hospital in Madrid, commented, “This is the most impressive cohort in terms of progression-free survival that we have seen in the neuroendocrine tumors … especially since the comparator arm is a really active one that we are doing in routine practice.”
177Lu-Dotatate belongs to a drug category called peptide receptor radionuclide therapy and is composed of a lutetium radionuclide chelated to a peptide. The 177Lutetium-labeled somatostatin analogue peptide targets somatostatin receptors, which are overexpressed in about 80% of neuroendocrine tumors (NETs).
177Lu-Dotatate has received orphan drug status from the Food and Drug Administration and the European Medicines Agency and in April 2015 also was granted fast-track designation by the FDA.
NETTER-1 enrolled 230 patients with metastatic or locally advanced, inoperable midgut NETs, functioning or not, and evenly randomized them to four doses of 7.4 GBq 177Lu-Dotatate intravenously over 8 weeks plus octreotide LAR 30 mg or to octreotide LAR 60 mg every 28 days given as a deep intragluteal injection. The ileum was the primary tumor site in three-fourths of patients and the liver the site of metastasis in about 83%.
Three-fourths of patients received all four doses of 177Lu-Dotatate and no dose-modifying toxicity was observed in 95% of all 111 treated patients, Dr. Ruszniewski said.
An interim analysis suggested increased overall survival (13 deaths vs. 22 deaths; P less than .018), but the data are immature and need to be confirmed by final analysis, he said.
Treatment-related adverse events of any grade were reported in 86% of patients given 177Lu-Dotatate and 31% on octreotide LAR 60 mg.
Treatment-related serious events occurred in 10 patients in the 177Lu-Dotatate arm vs. 1 in the octreotide arm, with withdrawals because of treatment-related adverse events in 5 vs. 0 patients, respectively.
Serious adverse events related to 177Lu-Dotatate included, but were not limited to, lymphocytopenia in seven patients, thrombocytopenia in three, acute kidney injury in two, and one case each of renal failure and portal hypertension.
When asked in a press briefing whether 177Lu-Dotatate could induce long-term DNA damage after hitting its target, Dr. Ruszniewski said a substudy in 20 unrelated patients will provide pharmacokinetic data on the fate of the radionuclide.
“What we know from phase I and II is that this is probably possible, but rare,” he said. “The two organs that should be carefully watched are the bone marrow and the kidneys.”
To reduce kidney damage, amino acids are infused at the same time as the radionuclide. Myelodysplastic syndrome might occur in 3% to 4% of patients, he added.
The investigators called for additional studies of 177Lu-Dotatate in other types of NETs such as pancreatic and bronchial.
When it was noted that the approved radioactive agent, radium-223 dichloride (Xofigo) also has very good data in pancreatic cancer but is often used behind other drugs because it is a radiopharmaceutical, Dr. Ruszniewski dismissed the suggestion and said NETs are a completely different disease.
Discussant Dr. Grande, however, said that there are logistical considerations surrounding 177-Lu-Dotatate, such as how clinicians would request it, whether it will be widely available, and where it would be delivered.
No special room is needed to treat patients with 177-Lu-Dotatate, but patient urine does have to be controlled, Dr. Ruszniewski noted.
On Twitter @pwendl
AT EUROPEAN CANCER CONGRESS 2015
Key clinical point: 177Lu-Dotatate plus octreotide LAR was superior to a double-dose of octreotide LAR in terms of progression-free survival and overall response in progressive midgut neuroendocrine tumors.
Major finding: Median progression-free survival was not reached for 177Lu-Dotatate plus octreotide LAR; it was 8.4 months for high-dose octreotide LAR (hazard ratio, 0.2; P less than .001).
Data source: Phase III trial in 230 patients with progressive midgut NETs.
Disclosures: Advanced Accelerator Applications funded the study. Dr. Ruszniewski reported serving as an advisor to AAA and has received honoraria and research funding from AAA, Ipsen, and Novartis.
Reattaching intercostals fails to squelch spinal cord ischemia in TAAA repairs
CHICAGO – Intercostal artery reimplantation fails to significantly reduce spinal cord injury following thoracoabdominal aortic aneurysm surgery, results of a large retrospective study show.
“Although there was a small decrease in spinal cord ischemia with ICAR, reattaching the intercostals did not produce a statistically significant reduction in spinal cord ischemia, even in the highest risk patients,” Dr. Charles W. Acher of the University of Wisconsin–Madison, said at the annual meeting of the Midwestern Vascular Surgical Society.
Intercostal artery reimplantation (ICAR) is one of several strategies that have been used to prevent spinal cord ischemia (SCI), paraplegia, and paraparesis that occurs from the interruption of the blood supply to intercostal arteries (ICAs) during thoracoabdominal aortic aneurysm (TAAA) repair.
Surgeons at UW–Madison adopted the ICAR strategy in 2005and now reimplant open ICAs located at T7-L2 in all Type I, II, and III TAAAs, using a previously published technique (J Surg Res. 2009;154:99-104).
Using a prospectively maintained database, the current analysis sought to compare outcomes between 540 patients who had TAAA surgery during 1989-2004 when open ICAs were ligated and 265 patients who had surgery during 2005-2013 with ICAR.The surgical technique for both groups was cross clamp without assisted circulation. The anesthetic technique was also uniform during the study period and included moderate systemic hypothermia (32° - 33° C); spinal fluid drainage (spinal fluid pressure less than 5 mm Hg); naloxone 1 mcg/kg per hour; use of mannitol, methylprednisolone, and barbiturate burst suppression; goal-directed therapy for a mean arterial pressure of 90-100 mm Hg and cardiac index of 2.5 L per minute/meter2; and proactive component blood therapy to avoid anemia, hypovolemia, and hypertension.
Aneurysm extent, acuity, mortality, renal failure, and pulmonary failure were the same in both groups.
The incidence of SCI was similar in all TAAAs at 5.25% without ICAR and 3.4% with ICAR (P = .23) and in the subset of patients with Type I, II, and III aneurysms (8.8% vs. 5.1%; P = .152), Dr. Acher reported on behalf of lead author and his colleague, Dr. Martha M. Wynn.
Interestingly, ICAR patients had more dissections than did the open ICA ligation patients (18% vs. 15%; P = .0016), more previous aortic surgery (47% vs. 31%; P = .0004), and longer renal ischemia time (61 minutes vs. 53 minutes; P = .0001), but had a shorter length of stay (14 days vs. 22 days; P = .0001) and were younger (mean age, 66 years vs. 70 years; P = .0001).
In a multivariate model of all TAAAs, significant predictors of spinal cord ischemia/injury were type II TAAA (odds ratio, 7.59; P = .0001), dissection (OR, 4.25; P = .0015), age as a continuous variable (P = .0085), and acute TAAA (OR, 2.1; P = .0525), Dr. Acher said. Time period of surgery, and therefore ICAR, was not significant (OR, 0.78; P = .55).
ICAR also failed to achieve significance as an SCI predictor in a subanalysis restricted to the highest-risk patients, defined as those having Type II TAAA, dissection, and acute surgery (OR, 0.67; P = .3387).
“Interrupting blood supply to the spinal cord causes spinal cord ischemia that can be mitigated almost entirely by physiologic interventions that increase spinal cord ischemic tolerance and collateral network perfusion during and after surgery,” Dr. Acher said. “Although the cause of SCI in TAAA surgery is anatomic, prevention of the injury is largely physiologic.”
During a discussion of the study, Dr. Acher surprised the audience by saying the findings have not changed current practice at the university. He cited several reasons, observing that there were more dissections in the ICAR group, and most of the ischemia in the ICAR group was delayed, suggesting that more patients could be rescued. In addition, there was a slight downward trend in spinal cord injury and immediate paraplegia with ICAR, however, these were not statistically significant.
“Because of those things, I still think it’s valuable, particularly in patients that are at highest risk, which are the dissections, with lots of open intercostals, but the emphasis should still be on physiologic parameters,” he said. “If you want to salvage patients, that’s the most important thing.
“Even if ICAR were ever shown to be statistically significant in a larger patient population, any role it has in reducing spinal cord injury would be extremely small,” he added in an interview.
The authors reported having no conflicts of interest.
Spinal cord ischemia is a rare but devastating complication of thoracoabdominal aneurysm repair. Crawford and his colleagues documented in 1993 an incidence of spinal cord ischemia (SCI) as high as 30% for extensive thoracoabdominal repairs. Efforts to diminish the risk of SCI were concentrated in identifying and preserving the direct arterial perfusion to the spinal cord from segmental arteries but continued experimental and clinical experience have suggested that multiple factors contribute to SCI.
 |
Dr. Luis A. Sanchez |
Some generally accepted principles for minimizing SCI include hypothermia, distal aortic perfusion with atriofemoral bypass or partial cardiopulmonary bypass, cerebrospinal fluid drainage, and avoidance of hemodynamic instability. Reimplantation of intercostal branches has been suggested as an adjunct to these techniques by some investigators with limited data to support its generalized application. More recently, a growing body of evidence supports the concept of a collateral network that can support the perfusion to the spinal cord after interruption of multiple intercostal arteries and the importance of the hypogastric and subclavian arteries as critical branches that perfuse the spinal collateral network.
The retrospective review of the extensive experience at the University of Wisconsin in Madison supports the concept that “physiologic interventions that increase spinal cord tolerance and collateral network perfusion during and after surgery” are more important than the reimplantation of intercostal vessels during this complex procedure, even in patients considered at the highest risk for SCI. Intercostal artery reimplantation failed to achieve significance as an SCI predictor when comparing two large cohorts of patients (540 vs. 265) treated with intercostal ligation vs. reimplantation. Increasingly, available data support the concept of a collateral network that maintains perfusion to the spinal cord after intercostal artery occlusion.
Additional new concepts and techniques including a two-stage approach for extensive thoracoabdominal repair, preliminary occlusion of some segmental arteries, and the use of hybrid and endovascular techniques may further decrease the incidence of SCI by taking advantage of the collateral network and allow some preconditioning of the spinal cord. Fortunately for these challenging patients, significant advances continue to be made to better understand and prevent spinal cord ischemia.
Dr. Luis A. Sanchez is Chief, Section of Vascular Surgery and the Gregorio A. Sicard Distinguished Professor of Surgery and Radiology, Department of Surgery, Washington University in St. Louis.
Spinal cord ischemia is a rare but devastating complication of thoracoabdominal aneurysm repair. Crawford and his colleagues documented in 1993 an incidence of spinal cord ischemia (SCI) as high as 30% for extensive thoracoabdominal repairs. Efforts to diminish the risk of SCI were concentrated in identifying and preserving the direct arterial perfusion to the spinal cord from segmental arteries but continued experimental and clinical experience have suggested that multiple factors contribute to SCI.
|
Dr. Luis A. Sanchez |
Some generally accepted principles for minimizing SCI include hypothermia, distal aortic perfusion with atriofemoral bypass or partial cardiopulmonary bypass, cerebrospinal fluid drainage, and avoidance of hemodynamic instability. Reimplantation of intercostal branches has been suggested as an adjunct to these techniques by some investigators with limited data to support its generalized application. More recently, a growing body of evidence supports the concept of a collateral network that can support the perfusion to the spinal cord after interruption of multiple intercostal arteries and the importance of the hypogastric and subclavian arteries as critical branches that perfuse the spinal collateral network.
The retrospective review of the extensive experience at the University of Wisconsin in Madison supports the concept that “physiologic interventions that increase spinal cord tolerance and collateral network perfusion during and after surgery” are more important than the reimplantation of intercostal vessels during this complex procedure, even in patients considered at the highest risk for SCI. Intercostal artery reimplantation failed to achieve significance as an SCI predictor when comparing two large cohorts of patients (540 vs. 265) treated with intercostal ligation vs. reimplantation. Increasingly, available data support the concept of a collateral network that maintains perfusion to the spinal cord after intercostal artery occlusion.
Additional new concepts and techniques including a two-stage approach for extensive thoracoabdominal repair, preliminary occlusion of some segmental arteries, and the use of hybrid and endovascular techniques may further decrease the incidence of SCI by taking advantage of the collateral network and allow some preconditioning of the spinal cord. Fortunately for these challenging patients, significant advances continue to be made to better understand and prevent spinal cord ischemia.
Dr. Luis A. Sanchez is Chief, Section of Vascular Surgery and the Gregorio A. Sicard Distinguished Professor of Surgery and Radiology, Department of Surgery, Washington University in St. Louis.
Spinal cord ischemia is a rare but devastating complication of thoracoabdominal aneurysm repair. Crawford and his colleagues documented in 1993 an incidence of spinal cord ischemia (SCI) as high as 30% for extensive thoracoabdominal repairs. Efforts to diminish the risk of SCI were concentrated in identifying and preserving the direct arterial perfusion to the spinal cord from segmental arteries but continued experimental and clinical experience have suggested that multiple factors contribute to SCI.
|
Dr. Luis A. Sanchez |
Some generally accepted principles for minimizing SCI include hypothermia, distal aortic perfusion with atriofemoral bypass or partial cardiopulmonary bypass, cerebrospinal fluid drainage, and avoidance of hemodynamic instability. Reimplantation of intercostal branches has been suggested as an adjunct to these techniques by some investigators with limited data to support its generalized application. More recently, a growing body of evidence supports the concept of a collateral network that can support the perfusion to the spinal cord after interruption of multiple intercostal arteries and the importance of the hypogastric and subclavian arteries as critical branches that perfuse the spinal collateral network.
The retrospective review of the extensive experience at the University of Wisconsin in Madison supports the concept that “physiologic interventions that increase spinal cord tolerance and collateral network perfusion during and after surgery” are more important than the reimplantation of intercostal vessels during this complex procedure, even in patients considered at the highest risk for SCI. Intercostal artery reimplantation failed to achieve significance as an SCI predictor when comparing two large cohorts of patients (540 vs. 265) treated with intercostal ligation vs. reimplantation. Increasingly, available data support the concept of a collateral network that maintains perfusion to the spinal cord after intercostal artery occlusion.
Additional new concepts and techniques including a two-stage approach for extensive thoracoabdominal repair, preliminary occlusion of some segmental arteries, and the use of hybrid and endovascular techniques may further decrease the incidence of SCI by taking advantage of the collateral network and allow some preconditioning of the spinal cord. Fortunately for these challenging patients, significant advances continue to be made to better understand and prevent spinal cord ischemia.
Dr. Luis A. Sanchez is Chief, Section of Vascular Surgery and the Gregorio A. Sicard Distinguished Professor of Surgery and Radiology, Department of Surgery, Washington University in St. Louis.
CHICAGO – Intercostal artery reimplantation fails to significantly reduce spinal cord injury following thoracoabdominal aortic aneurysm surgery, results of a large retrospective study show.
“Although there was a small decrease in spinal cord ischemia with ICAR, reattaching the intercostals did not produce a statistically significant reduction in spinal cord ischemia, even in the highest risk patients,” Dr. Charles W. Acher of the University of Wisconsin–Madison, said at the annual meeting of the Midwestern Vascular Surgical Society.
Intercostal artery reimplantation (ICAR) is one of several strategies that have been used to prevent spinal cord ischemia (SCI), paraplegia, and paraparesis that occurs from the interruption of the blood supply to intercostal arteries (ICAs) during thoracoabdominal aortic aneurysm (TAAA) repair.
Surgeons at UW–Madison adopted the ICAR strategy in 2005and now reimplant open ICAs located at T7-L2 in all Type I, II, and III TAAAs, using a previously published technique (J Surg Res. 2009;154:99-104).
Using a prospectively maintained database, the current analysis sought to compare outcomes between 540 patients who had TAAA surgery during 1989-2004 when open ICAs were ligated and 265 patients who had surgery during 2005-2013 with ICAR.The surgical technique for both groups was cross clamp without assisted circulation. The anesthetic technique was also uniform during the study period and included moderate systemic hypothermia (32° - 33° C); spinal fluid drainage (spinal fluid pressure less than 5 mm Hg); naloxone 1 mcg/kg per hour; use of mannitol, methylprednisolone, and barbiturate burst suppression; goal-directed therapy for a mean arterial pressure of 90-100 mm Hg and cardiac index of 2.5 L per minute/meter2; and proactive component blood therapy to avoid anemia, hypovolemia, and hypertension.
Aneurysm extent, acuity, mortality, renal failure, and pulmonary failure were the same in both groups.
The incidence of SCI was similar in all TAAAs at 5.25% without ICAR and 3.4% with ICAR (P = .23) and in the subset of patients with Type I, II, and III aneurysms (8.8% vs. 5.1%; P = .152), Dr. Acher reported on behalf of lead author and his colleague, Dr. Martha M. Wynn.
Interestingly, ICAR patients had more dissections than did the open ICA ligation patients (18% vs. 15%; P = .0016), more previous aortic surgery (47% vs. 31%; P = .0004), and longer renal ischemia time (61 minutes vs. 53 minutes; P = .0001), but had a shorter length of stay (14 days vs. 22 days; P = .0001) and were younger (mean age, 66 years vs. 70 years; P = .0001).
In a multivariate model of all TAAAs, significant predictors of spinal cord ischemia/injury were type II TAAA (odds ratio, 7.59; P = .0001), dissection (OR, 4.25; P = .0015), age as a continuous variable (P = .0085), and acute TAAA (OR, 2.1; P = .0525), Dr. Acher said. Time period of surgery, and therefore ICAR, was not significant (OR, 0.78; P = .55).
ICAR also failed to achieve significance as an SCI predictor in a subanalysis restricted to the highest-risk patients, defined as those having Type II TAAA, dissection, and acute surgery (OR, 0.67; P = .3387).
“Interrupting blood supply to the spinal cord causes spinal cord ischemia that can be mitigated almost entirely by physiologic interventions that increase spinal cord ischemic tolerance and collateral network perfusion during and after surgery,” Dr. Acher said. “Although the cause of SCI in TAAA surgery is anatomic, prevention of the injury is largely physiologic.”
During a discussion of the study, Dr. Acher surprised the audience by saying the findings have not changed current practice at the university. He cited several reasons, observing that there were more dissections in the ICAR group, and most of the ischemia in the ICAR group was delayed, suggesting that more patients could be rescued. In addition, there was a slight downward trend in spinal cord injury and immediate paraplegia with ICAR, however, these were not statistically significant.
“Because of those things, I still think it’s valuable, particularly in patients that are at highest risk, which are the dissections, with lots of open intercostals, but the emphasis should still be on physiologic parameters,” he said. “If you want to salvage patients, that’s the most important thing.
“Even if ICAR were ever shown to be statistically significant in a larger patient population, any role it has in reducing spinal cord injury would be extremely small,” he added in an interview.
The authors reported having no conflicts of interest.
CHICAGO – Intercostal artery reimplantation fails to significantly reduce spinal cord injury following thoracoabdominal aortic aneurysm surgery, results of a large retrospective study show.
“Although there was a small decrease in spinal cord ischemia with ICAR, reattaching the intercostals did not produce a statistically significant reduction in spinal cord ischemia, even in the highest risk patients,” Dr. Charles W. Acher of the University of Wisconsin–Madison, said at the annual meeting of the Midwestern Vascular Surgical Society.
Intercostal artery reimplantation (ICAR) is one of several strategies that have been used to prevent spinal cord ischemia (SCI), paraplegia, and paraparesis that occurs from the interruption of the blood supply to intercostal arteries (ICAs) during thoracoabdominal aortic aneurysm (TAAA) repair.
Surgeons at UW–Madison adopted the ICAR strategy in 2005and now reimplant open ICAs located at T7-L2 in all Type I, II, and III TAAAs, using a previously published technique (J Surg Res. 2009;154:99-104).
Using a prospectively maintained database, the current analysis sought to compare outcomes between 540 patients who had TAAA surgery during 1989-2004 when open ICAs were ligated and 265 patients who had surgery during 2005-2013 with ICAR.The surgical technique for both groups was cross clamp without assisted circulation. The anesthetic technique was also uniform during the study period and included moderate systemic hypothermia (32° - 33° C); spinal fluid drainage (spinal fluid pressure less than 5 mm Hg); naloxone 1 mcg/kg per hour; use of mannitol, methylprednisolone, and barbiturate burst suppression; goal-directed therapy for a mean arterial pressure of 90-100 mm Hg and cardiac index of 2.5 L per minute/meter2; and proactive component blood therapy to avoid anemia, hypovolemia, and hypertension.
Aneurysm extent, acuity, mortality, renal failure, and pulmonary failure were the same in both groups.
The incidence of SCI was similar in all TAAAs at 5.25% without ICAR and 3.4% with ICAR (P = .23) and in the subset of patients with Type I, II, and III aneurysms (8.8% vs. 5.1%; P = .152), Dr. Acher reported on behalf of lead author and his colleague, Dr. Martha M. Wynn.
Interestingly, ICAR patients had more dissections than did the open ICA ligation patients (18% vs. 15%; P = .0016), more previous aortic surgery (47% vs. 31%; P = .0004), and longer renal ischemia time (61 minutes vs. 53 minutes; P = .0001), but had a shorter length of stay (14 days vs. 22 days; P = .0001) and were younger (mean age, 66 years vs. 70 years; P = .0001).
In a multivariate model of all TAAAs, significant predictors of spinal cord ischemia/injury were type II TAAA (odds ratio, 7.59; P = .0001), dissection (OR, 4.25; P = .0015), age as a continuous variable (P = .0085), and acute TAAA (OR, 2.1; P = .0525), Dr. Acher said. Time period of surgery, and therefore ICAR, was not significant (OR, 0.78; P = .55).
ICAR also failed to achieve significance as an SCI predictor in a subanalysis restricted to the highest-risk patients, defined as those having Type II TAAA, dissection, and acute surgery (OR, 0.67; P = .3387).
“Interrupting blood supply to the spinal cord causes spinal cord ischemia that can be mitigated almost entirely by physiologic interventions that increase spinal cord ischemic tolerance and collateral network perfusion during and after surgery,” Dr. Acher said. “Although the cause of SCI in TAAA surgery is anatomic, prevention of the injury is largely physiologic.”
During a discussion of the study, Dr. Acher surprised the audience by saying the findings have not changed current practice at the university. He cited several reasons, observing that there were more dissections in the ICAR group, and most of the ischemia in the ICAR group was delayed, suggesting that more patients could be rescued. In addition, there was a slight downward trend in spinal cord injury and immediate paraplegia with ICAR, however, these were not statistically significant.
“Because of those things, I still think it’s valuable, particularly in patients that are at highest risk, which are the dissections, with lots of open intercostals, but the emphasis should still be on physiologic parameters,” he said. “If you want to salvage patients, that’s the most important thing.
“Even if ICAR were ever shown to be statistically significant in a larger patient population, any role it has in reducing spinal cord injury would be extremely small,” he added in an interview.
The authors reported having no conflicts of interest.
AT MIDWESTERN VASCULAR 2015
Key clinical point: Intercostal artery reimplantation (ICAR) did not produce a significant reduction in spinal cord ischemia following thoracoabdominal aortic aneurysm repair, even in the highest risk patients.
Major finding: ICAR was not a significant predictor of spinal cord ischemia (OR, 0.78; P = .55).
Data source: Retrospective analysis of 805 patients undergoing TAAA with or without ICAR.
Disclosures: The authors reported having no conflicts of interest.
Women dogged by unplanned readmissions after aortic surgery
CHICAGO – Women undergoing aortic surgery have a 30% higher chance of unplanned readmission within 30 days than men.
This occurs despite a significantly longer length of stay (6.4 vs. 4.8 days; P < .001), Dr. Benjamin Flink said at the annual meeting of the Midwestern Vascular Surgical Society.
Women undergoing aortic surgery are known to have higher morbidity and mortality with respect to cardiovascular events and infections, but no studies have specifically looked at sex disparities in readmission following aortic surgery, he said.
“We feel gender disparities are an understudied area of surgical care and there is a lot of work to be done in reducing these differences,” principal investigator Dr. Shipra Arya said in an interview.
To better examine this issue, Dr. Arya and Dr. Flink, both of Emory University in Atlanta, and investigators at the University of Michigan identified all patients undergoing open or endovascular abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA), and thoracoabdominal aortic aneurysm (TAAA) repair from 2011 to 2013 who were in the American College of Surgeons National Surgical Quality Improvement Program (ACS/NSQIP) database. Of the 18,977 patients, 23% were women.
Use of endovascular procedures varied significantly by sex, with women having significantly fewer endovascular AAA (68.8% vs. 77.1%; P less than .001) and TAAA (43.2% vs. 65.2%; P < .001) repairs than men. Endovascular TAA repairs were similar in women and men (96.1% vs. 95.6%; P = .8), Dr. Flink said.
Overall, 1,541 patients (8.1%) experienced the primary outcome of an unplanned readmission within 30 days, with a significantly higher risk observed in women than men (10.1% vs. 7.6%; P less than .001).
This risk persisted for most aneurysm types, with women having a higher risk of readmission for AAA (9.4% vs. 7.3%; P less than .001) and TAAA (13.7% vs. 8.3%; P = .03) aneurysms, but not TAAs (13% vs. 12.5%; P = .8), he said.
The overall length of stay was 5.2 days. Women stayed 1.6 days longer than men (data above), readmitted patients stayed 1 day longer during their index hospitalization than patients who avoided readmission (5.1 days vs. 4.1 days; P less than .001), and open-repair patients stayed more than twice as long as endovascular patients (10.3 days vs. 3.7 days; P less than .001).
Patients discharged to home, however, had less than one-third the length of stay as those discharged to a facility other than home (4 days vs. 12.8 days; P less than .001).
Notably, women were discharged to a facility other than home nearly twice as often as men (20.4% vs. 10.6%; P less than .001), Dr. Flink said.
In multivariate analysis, the odds of an unplanned readmission were 30% higher for women than men after controlling for 13 variables (odds ratio, 1.3; 95% confidence interval, 1.14-1.48).
When the analysis was stratified by discharge destination, the higher odds of readmission among women remained for those discharged home (OR, 1.3; 95% CI, 1.12-1.51), but not when discharged to a skilled or rehabilitation facility (OR, 1.1; 95% CI, 0.83-1.45).
“Further study into the discharge planning process, social factors, and the use of rehabilitation is needed,” Dr. Flink said. “For example, why are we keeping women longer? Are we missing opportunities to better utilize rehabilitation in hospital? And what gender-specific social factors might be influencing unplanned readmissions that we’re currently not measuring?”
Dr. John Blebea of the University of Oklahoma, Tulsa, asked whether marital status was examined as an independent variable, “because I would suspect that’s the answer to the question. More women are widowed than men and therefore are less likely to have a spouse at home to take care of them, which would also explain why they’d be in the hospital longer.”
Unfortunately, that information is not available in the ACS/NSQIP database, but “I do agree that home-social factors are likely playing a role,” Dr. Flink responded.
Along the same vein, another attendee questioned whether the study accounted for frailty index scores. They were not, but the analysis included patients’ functional status as well as comorbidities such as congestive heart failure, stroke, peripheral arterial disease, and dialysis dependence that would limit their physical independence, Dr. Flink said.
Dr. Flink reported having no financial disclosures. Principal investigator Dr. Shipra Arya is funded by a research grant from the American Heart Association.
On Twitter @pwendl
CHICAGO – Women undergoing aortic surgery have a 30% higher chance of unplanned readmission within 30 days than men.
This occurs despite a significantly longer length of stay (6.4 vs. 4.8 days; P < .001), Dr. Benjamin Flink said at the annual meeting of the Midwestern Vascular Surgical Society.
Women undergoing aortic surgery are known to have higher morbidity and mortality with respect to cardiovascular events and infections, but no studies have specifically looked at sex disparities in readmission following aortic surgery, he said.
“We feel gender disparities are an understudied area of surgical care and there is a lot of work to be done in reducing these differences,” principal investigator Dr. Shipra Arya said in an interview.
To better examine this issue, Dr. Arya and Dr. Flink, both of Emory University in Atlanta, and investigators at the University of Michigan identified all patients undergoing open or endovascular abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA), and thoracoabdominal aortic aneurysm (TAAA) repair from 2011 to 2013 who were in the American College of Surgeons National Surgical Quality Improvement Program (ACS/NSQIP) database. Of the 18,977 patients, 23% were women.
Use of endovascular procedures varied significantly by sex, with women having significantly fewer endovascular AAA (68.8% vs. 77.1%; P less than .001) and TAAA (43.2% vs. 65.2%; P < .001) repairs than men. Endovascular TAA repairs were similar in women and men (96.1% vs. 95.6%; P = .8), Dr. Flink said.
Overall, 1,541 patients (8.1%) experienced the primary outcome of an unplanned readmission within 30 days, with a significantly higher risk observed in women than men (10.1% vs. 7.6%; P less than .001).
This risk persisted for most aneurysm types, with women having a higher risk of readmission for AAA (9.4% vs. 7.3%; P less than .001) and TAAA (13.7% vs. 8.3%; P = .03) aneurysms, but not TAAs (13% vs. 12.5%; P = .8), he said.
The overall length of stay was 5.2 days. Women stayed 1.6 days longer than men (data above), readmitted patients stayed 1 day longer during their index hospitalization than patients who avoided readmission (5.1 days vs. 4.1 days; P less than .001), and open-repair patients stayed more than twice as long as endovascular patients (10.3 days vs. 3.7 days; P less than .001).
Patients discharged to home, however, had less than one-third the length of stay as those discharged to a facility other than home (4 days vs. 12.8 days; P less than .001).
Notably, women were discharged to a facility other than home nearly twice as often as men (20.4% vs. 10.6%; P less than .001), Dr. Flink said.
In multivariate analysis, the odds of an unplanned readmission were 30% higher for women than men after controlling for 13 variables (odds ratio, 1.3; 95% confidence interval, 1.14-1.48).
When the analysis was stratified by discharge destination, the higher odds of readmission among women remained for those discharged home (OR, 1.3; 95% CI, 1.12-1.51), but not when discharged to a skilled or rehabilitation facility (OR, 1.1; 95% CI, 0.83-1.45).
“Further study into the discharge planning process, social factors, and the use of rehabilitation is needed,” Dr. Flink said. “For example, why are we keeping women longer? Are we missing opportunities to better utilize rehabilitation in hospital? And what gender-specific social factors might be influencing unplanned readmissions that we’re currently not measuring?”
Dr. John Blebea of the University of Oklahoma, Tulsa, asked whether marital status was examined as an independent variable, “because I would suspect that’s the answer to the question. More women are widowed than men and therefore are less likely to have a spouse at home to take care of them, which would also explain why they’d be in the hospital longer.”
Unfortunately, that information is not available in the ACS/NSQIP database, but “I do agree that home-social factors are likely playing a role,” Dr. Flink responded.
Along the same vein, another attendee questioned whether the study accounted for frailty index scores. They were not, but the analysis included patients’ functional status as well as comorbidities such as congestive heart failure, stroke, peripheral arterial disease, and dialysis dependence that would limit their physical independence, Dr. Flink said.
Dr. Flink reported having no financial disclosures. Principal investigator Dr. Shipra Arya is funded by a research grant from the American Heart Association.
On Twitter @pwendl
CHICAGO – Women undergoing aortic surgery have a 30% higher chance of unplanned readmission within 30 days than men.
This occurs despite a significantly longer length of stay (6.4 vs. 4.8 days; P < .001), Dr. Benjamin Flink said at the annual meeting of the Midwestern Vascular Surgical Society.
Women undergoing aortic surgery are known to have higher morbidity and mortality with respect to cardiovascular events and infections, but no studies have specifically looked at sex disparities in readmission following aortic surgery, he said.
“We feel gender disparities are an understudied area of surgical care and there is a lot of work to be done in reducing these differences,” principal investigator Dr. Shipra Arya said in an interview.
To better examine this issue, Dr. Arya and Dr. Flink, both of Emory University in Atlanta, and investigators at the University of Michigan identified all patients undergoing open or endovascular abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA), and thoracoabdominal aortic aneurysm (TAAA) repair from 2011 to 2013 who were in the American College of Surgeons National Surgical Quality Improvement Program (ACS/NSQIP) database. Of the 18,977 patients, 23% were women.
Use of endovascular procedures varied significantly by sex, with women having significantly fewer endovascular AAA (68.8% vs. 77.1%; P less than .001) and TAAA (43.2% vs. 65.2%; P < .001) repairs than men. Endovascular TAA repairs were similar in women and men (96.1% vs. 95.6%; P = .8), Dr. Flink said.
Overall, 1,541 patients (8.1%) experienced the primary outcome of an unplanned readmission within 30 days, with a significantly higher risk observed in women than men (10.1% vs. 7.6%; P less than .001).
This risk persisted for most aneurysm types, with women having a higher risk of readmission for AAA (9.4% vs. 7.3%; P less than .001) and TAAA (13.7% vs. 8.3%; P = .03) aneurysms, but not TAAs (13% vs. 12.5%; P = .8), he said.
The overall length of stay was 5.2 days. Women stayed 1.6 days longer than men (data above), readmitted patients stayed 1 day longer during their index hospitalization than patients who avoided readmission (5.1 days vs. 4.1 days; P less than .001), and open-repair patients stayed more than twice as long as endovascular patients (10.3 days vs. 3.7 days; P less than .001).
Patients discharged to home, however, had less than one-third the length of stay as those discharged to a facility other than home (4 days vs. 12.8 days; P less than .001).
Notably, women were discharged to a facility other than home nearly twice as often as men (20.4% vs. 10.6%; P less than .001), Dr. Flink said.
In multivariate analysis, the odds of an unplanned readmission were 30% higher for women than men after controlling for 13 variables (odds ratio, 1.3; 95% confidence interval, 1.14-1.48).
When the analysis was stratified by discharge destination, the higher odds of readmission among women remained for those discharged home (OR, 1.3; 95% CI, 1.12-1.51), but not when discharged to a skilled or rehabilitation facility (OR, 1.1; 95% CI, 0.83-1.45).
“Further study into the discharge planning process, social factors, and the use of rehabilitation is needed,” Dr. Flink said. “For example, why are we keeping women longer? Are we missing opportunities to better utilize rehabilitation in hospital? And what gender-specific social factors might be influencing unplanned readmissions that we’re currently not measuring?”
Dr. John Blebea of the University of Oklahoma, Tulsa, asked whether marital status was examined as an independent variable, “because I would suspect that’s the answer to the question. More women are widowed than men and therefore are less likely to have a spouse at home to take care of them, which would also explain why they’d be in the hospital longer.”
Unfortunately, that information is not available in the ACS/NSQIP database, but “I do agree that home-social factors are likely playing a role,” Dr. Flink responded.
Along the same vein, another attendee questioned whether the study accounted for frailty index scores. They were not, but the analysis included patients’ functional status as well as comorbidities such as congestive heart failure, stroke, peripheral arterial disease, and dialysis dependence that would limit their physical independence, Dr. Flink said.
Dr. Flink reported having no financial disclosures. Principal investigator Dr. Shipra Arya is funded by a research grant from the American Heart Association.
On Twitter @pwendl
AT MIDWESTERN VASCULAR 2015
Key clinical point: Women undergoing aortic surgery are at higher risk for unplanned readmissions, compared with men, especially when discharged to home.
Major finding: The odds of an unplanned readmission at 30 days were 30% higher for women than men.
Data source: Retrospective study of 18,977 patients undergoing aortic aneurysm repair in the ACS/NSQIP database.
Disclosures: Dr. Flink reported having no financial disclosures. Principal investigator Dr. Shipra Arya is funded by a research grant from the American Heart Association.
VIDEO: Think immunotherapy first in relapsed NSCLC
VIENNA – Given atezolizumab’s success over chemotherapy in the recent POPLAR trial, is it time to think of immunotherapy as a first-line option for relapsed non–small-cell lung cancer?
“Several data sets, including POPLAR but also with other immune checkpoint inhibitors, have now shown that immunotherapy outcomes are superior to standard chemotherapy outcomes in the relapsed treatment of non–small-cell lung cancer,” noted POPLAR study author Dr. Johan Vansteenkiste of University Hospitals Leuven, Belgium.
In an interview at the European Cancer Congress 2015, Dr. Vansteenkiste discussed the potential for immunotherapy to become a standard relapse treatment for NSCLC, either alone or as combination treatment with chemotherapy.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
VIENNA – Given atezolizumab’s success over chemotherapy in the recent POPLAR trial, is it time to think of immunotherapy as a first-line option for relapsed non–small-cell lung cancer?
“Several data sets, including POPLAR but also with other immune checkpoint inhibitors, have now shown that immunotherapy outcomes are superior to standard chemotherapy outcomes in the relapsed treatment of non–small-cell lung cancer,” noted POPLAR study author Dr. Johan Vansteenkiste of University Hospitals Leuven, Belgium.
In an interview at the European Cancer Congress 2015, Dr. Vansteenkiste discussed the potential for immunotherapy to become a standard relapse treatment for NSCLC, either alone or as combination treatment with chemotherapy.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
VIENNA – Given atezolizumab’s success over chemotherapy in the recent POPLAR trial, is it time to think of immunotherapy as a first-line option for relapsed non–small-cell lung cancer?
“Several data sets, including POPLAR but also with other immune checkpoint inhibitors, have now shown that immunotherapy outcomes are superior to standard chemotherapy outcomes in the relapsed treatment of non–small-cell lung cancer,” noted POPLAR study author Dr. Johan Vansteenkiste of University Hospitals Leuven, Belgium.
In an interview at the European Cancer Congress 2015, Dr. Vansteenkiste discussed the potential for immunotherapy to become a standard relapse treatment for NSCLC, either alone or as combination treatment with chemotherapy.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
EXPERT ANALYSIS FROM THE EUROPEAN CANCER CONGRESS 2015
Two trials spotlight atezolizumab activity in advanced lung cancer
VIENNA – Immunotherapy with atezolizumab was active in patients with advanced lung cancer expressing PD-L1, regardless of the line of treatment in the BIRCH trial.
Additional follow-up in the sister POPLAR trial allowed atezolizumab to claim superior overall survival over docetaxel as second-line therapy in unselected lung cancer patients.
Atezolizumab is the second checkpoint inhibitor after nivolumab (Opdivo) to show superior efficacy to standard chemotherapy.
In both phase II trials, efficacy with the cell programmed death ligand 1 (PD-L1) inhibitor correlated with PD-L1 expression status.
“Higher PD-L1 expression correlates with higher responses” and may allow for identification of NSCLC patients who are likely to benefit from atezolizumab therapy, BIRCH study author Dr. Benjamin Besse of Institut Gustave Roussy in Villejuif, France, said at the European Cancer Congress 2015.
More than 30,000 patients were screened in 2014 for the single-arm trial, of which 34% were PD-L1 positive. In all, 667 patients with PD-L1-positive, locally advanced or metastatic non–small cell lung cancer (NSCLC) received atezolizumab 1,200 mg IV every 3 weeks as first-line or subsequent therapy. The Ventana SP142 immunohistochemistry assay was used to measure PD-L1 expression on both tumor cells (TC) and immune cells (IC). Roughly half of the patients (46%) had very high levels of PD-L1 expression (TC3 or IC3 status).
Patients were stratified into three cohorts: Cohort 1 had no prior therapy, cohort 2 had received one prior platinum-based chemotherapy, and cohort 3 had undergone at least two chemotherapies, including one platinum-based regimen.
The primary endpoint of objective response rate (ORR) by independent review was 19%, 17%, and 17% for the three cohorts, and increased to 26%, 24%, and 27%, respectively, when the analysis was restricted to patients with TC3 or IC3 status, Dr. Besse reported.
The majority of responses are ongoing (greater than 61% in TC3 or IC3).
Six-month overall survival rates were 82% in cohort 1, 76% in cohort 2, and 71% in cohort 3, and 79%, 80%, and 75%, respectively, in patients with TC3 or IC3 status.
The overall survival data are not yet mature after a median follow-up of 8.8 months, but the 6-month survival rates are consistent with results in POPLAR for the patients with two or three prior lines of therapy, he said.
Treatment-related grade 3/4 events occurred in 11% of 659 evaluable patients, with 5% of patients stopping atezolizumab due to an adverse event.
The safety profile is consistent with previous atezolizumab monotherapy trials, with no unexpected signals or differences in toxicity across cohorts, Dr. Besse said.
POPLAR took a different tack, evaluating the same dose of atezolizumab vs. docetaxel 75 mg/m2 IV every 3 weeks until disease progression, but in all-comers with metastatic or locally advanced NSCLC (second or third-line) who had progressed on a prior platinum therapy. The 287 patients were stratified by PD-L1 IC expression, histology, and number of prior chemotherapy regimens. In all, 16% of patients were TC3 or IC3.
The survival signal with atezolizumab was less impressive when seen at this year’s American Society of Clinical Oncology (ASCO) meeting, but with three additional months’ follow-up it now significantly favored immunotherapy over docetaxel in an intent-to-treat analysis (median 12.6 months vs. 9.7 months; hazard ratio, 0.73; P = .040).
“We have a minimum follow-up of 13 months, which means this part of the curve is less stable at the present time, but nonetheless the picture emerges that there will be ongoing separation of the curve,” study author Dr. Johan Vansteenkiste of University Hospitals KU Leuven, Belgium, said during the same immunotherapy session.
When the analysis was stratified by PD-L1 expression, the hazard ratios were 0.49 for the TC3 or IC3 patients with very high PD-L1 expression, 0.54 for TC2/3 or IC2/3 patients, 0.59 for TC1/2/3 or IC1/2/3 patients, and 1.04 for those without any PD-L1 expression.
“So there is a kind of a gradient of increasing benefit according to increased expression of PD-L1,” he said, adding that the same phenomenon was present for progression-free survival, with perhaps an even steeper gradient of increasing benefit according to intensity of staining.
The overall survival benefit was also observed in patients with squamous (HR, 0.80) and nonsquamous (HR, 0.69) histology.
The overall response rate was 15% for atezolizumab and docetaxel in the ITT analysis. Overall response differed in the subgroup with very high PD-L1 expression at 38% vs. 13%, respectively, but not in the other PD-L1 subgroups, Dr. Vansteenkiste said.
The median duration of response was 14.3 months with atezolizumab and 7.2 months with docetaxel (HR, 0.41; P = .033), with most responses ongoing, he said.
Invited discussant for both studies, Dr. Luis Paz-Ares of Hospital Universitario Virgen del Rocio in Seville, Spain, said the POPLAR overall survival results align very closely with those he reported at ASCO in the phase III CheckMate 057 study for nivolumab vs. docetaxel (median OS 12.2 months vs. 9.4 months).
“One trial actually confirms to the other, even though we are talking about two different agents from the same class and in different scenarios – phase II and phase III,” he said.
Although somewhat immature, the survival results from BIRCH are consistent with POPLAR and other phase II trials with other agents of this class, Dr. Paz-Ares said. What is yet to be determined is whether first-line patients benefit more from immunotherapy, possibly because the immune system is stronger at that point.
Dr. Martin Reck of Hospital Grosshansdorf, Germany, said atezolizumab is set to substantially change treatment strategies for patients with refractory lung cancer.
“In particular, the option for long-lasting responses and stabilization in combination with an attractive tolerability profile will impact clinical practice,” he said in a statement. “Whether patients should be selected using a biomarker strategy still needs to be determined and remains a significant challenge based on the multiple different companion diagnostics that are in use for the particular agents.”
On Twitter @pwendl
VIENNA – Immunotherapy with atezolizumab was active in patients with advanced lung cancer expressing PD-L1, regardless of the line of treatment in the BIRCH trial.
Additional follow-up in the sister POPLAR trial allowed atezolizumab to claim superior overall survival over docetaxel as second-line therapy in unselected lung cancer patients.
Atezolizumab is the second checkpoint inhibitor after nivolumab (Opdivo) to show superior efficacy to standard chemotherapy.
In both phase II trials, efficacy with the cell programmed death ligand 1 (PD-L1) inhibitor correlated with PD-L1 expression status.
“Higher PD-L1 expression correlates with higher responses” and may allow for identification of NSCLC patients who are likely to benefit from atezolizumab therapy, BIRCH study author Dr. Benjamin Besse of Institut Gustave Roussy in Villejuif, France, said at the European Cancer Congress 2015.
More than 30,000 patients were screened in 2014 for the single-arm trial, of which 34% were PD-L1 positive. In all, 667 patients with PD-L1-positive, locally advanced or metastatic non–small cell lung cancer (NSCLC) received atezolizumab 1,200 mg IV every 3 weeks as first-line or subsequent therapy. The Ventana SP142 immunohistochemistry assay was used to measure PD-L1 expression on both tumor cells (TC) and immune cells (IC). Roughly half of the patients (46%) had very high levels of PD-L1 expression (TC3 or IC3 status).
Patients were stratified into three cohorts: Cohort 1 had no prior therapy, cohort 2 had received one prior platinum-based chemotherapy, and cohort 3 had undergone at least two chemotherapies, including one platinum-based regimen.
The primary endpoint of objective response rate (ORR) by independent review was 19%, 17%, and 17% for the three cohorts, and increased to 26%, 24%, and 27%, respectively, when the analysis was restricted to patients with TC3 or IC3 status, Dr. Besse reported.
The majority of responses are ongoing (greater than 61% in TC3 or IC3).
Six-month overall survival rates were 82% in cohort 1, 76% in cohort 2, and 71% in cohort 3, and 79%, 80%, and 75%, respectively, in patients with TC3 or IC3 status.
The overall survival data are not yet mature after a median follow-up of 8.8 months, but the 6-month survival rates are consistent with results in POPLAR for the patients with two or three prior lines of therapy, he said.
Treatment-related grade 3/4 events occurred in 11% of 659 evaluable patients, with 5% of patients stopping atezolizumab due to an adverse event.
The safety profile is consistent with previous atezolizumab monotherapy trials, with no unexpected signals or differences in toxicity across cohorts, Dr. Besse said.
POPLAR took a different tack, evaluating the same dose of atezolizumab vs. docetaxel 75 mg/m2 IV every 3 weeks until disease progression, but in all-comers with metastatic or locally advanced NSCLC (second or third-line) who had progressed on a prior platinum therapy. The 287 patients were stratified by PD-L1 IC expression, histology, and number of prior chemotherapy regimens. In all, 16% of patients were TC3 or IC3.
The survival signal with atezolizumab was less impressive when seen at this year’s American Society of Clinical Oncology (ASCO) meeting, but with three additional months’ follow-up it now significantly favored immunotherapy over docetaxel in an intent-to-treat analysis (median 12.6 months vs. 9.7 months; hazard ratio, 0.73; P = .040).
“We have a minimum follow-up of 13 months, which means this part of the curve is less stable at the present time, but nonetheless the picture emerges that there will be ongoing separation of the curve,” study author Dr. Johan Vansteenkiste of University Hospitals KU Leuven, Belgium, said during the same immunotherapy session.
When the analysis was stratified by PD-L1 expression, the hazard ratios were 0.49 for the TC3 or IC3 patients with very high PD-L1 expression, 0.54 for TC2/3 or IC2/3 patients, 0.59 for TC1/2/3 or IC1/2/3 patients, and 1.04 for those without any PD-L1 expression.
“So there is a kind of a gradient of increasing benefit according to increased expression of PD-L1,” he said, adding that the same phenomenon was present for progression-free survival, with perhaps an even steeper gradient of increasing benefit according to intensity of staining.
The overall survival benefit was also observed in patients with squamous (HR, 0.80) and nonsquamous (HR, 0.69) histology.
The overall response rate was 15% for atezolizumab and docetaxel in the ITT analysis. Overall response differed in the subgroup with very high PD-L1 expression at 38% vs. 13%, respectively, but not in the other PD-L1 subgroups, Dr. Vansteenkiste said.
The median duration of response was 14.3 months with atezolizumab and 7.2 months with docetaxel (HR, 0.41; P = .033), with most responses ongoing, he said.
Invited discussant for both studies, Dr. Luis Paz-Ares of Hospital Universitario Virgen del Rocio in Seville, Spain, said the POPLAR overall survival results align very closely with those he reported at ASCO in the phase III CheckMate 057 study for nivolumab vs. docetaxel (median OS 12.2 months vs. 9.4 months).
“One trial actually confirms to the other, even though we are talking about two different agents from the same class and in different scenarios – phase II and phase III,” he said.
Although somewhat immature, the survival results from BIRCH are consistent with POPLAR and other phase II trials with other agents of this class, Dr. Paz-Ares said. What is yet to be determined is whether first-line patients benefit more from immunotherapy, possibly because the immune system is stronger at that point.
Dr. Martin Reck of Hospital Grosshansdorf, Germany, said atezolizumab is set to substantially change treatment strategies for patients with refractory lung cancer.
“In particular, the option for long-lasting responses and stabilization in combination with an attractive tolerability profile will impact clinical practice,” he said in a statement. “Whether patients should be selected using a biomarker strategy still needs to be determined and remains a significant challenge based on the multiple different companion diagnostics that are in use for the particular agents.”
On Twitter @pwendl
VIENNA – Immunotherapy with atezolizumab was active in patients with advanced lung cancer expressing PD-L1, regardless of the line of treatment in the BIRCH trial.
Additional follow-up in the sister POPLAR trial allowed atezolizumab to claim superior overall survival over docetaxel as second-line therapy in unselected lung cancer patients.
Atezolizumab is the second checkpoint inhibitor after nivolumab (Opdivo) to show superior efficacy to standard chemotherapy.
In both phase II trials, efficacy with the cell programmed death ligand 1 (PD-L1) inhibitor correlated with PD-L1 expression status.
“Higher PD-L1 expression correlates with higher responses” and may allow for identification of NSCLC patients who are likely to benefit from atezolizumab therapy, BIRCH study author Dr. Benjamin Besse of Institut Gustave Roussy in Villejuif, France, said at the European Cancer Congress 2015.
More than 30,000 patients were screened in 2014 for the single-arm trial, of which 34% were PD-L1 positive. In all, 667 patients with PD-L1-positive, locally advanced or metastatic non–small cell lung cancer (NSCLC) received atezolizumab 1,200 mg IV every 3 weeks as first-line or subsequent therapy. The Ventana SP142 immunohistochemistry assay was used to measure PD-L1 expression on both tumor cells (TC) and immune cells (IC). Roughly half of the patients (46%) had very high levels of PD-L1 expression (TC3 or IC3 status).
Patients were stratified into three cohorts: Cohort 1 had no prior therapy, cohort 2 had received one prior platinum-based chemotherapy, and cohort 3 had undergone at least two chemotherapies, including one platinum-based regimen.
The primary endpoint of objective response rate (ORR) by independent review was 19%, 17%, and 17% for the three cohorts, and increased to 26%, 24%, and 27%, respectively, when the analysis was restricted to patients with TC3 or IC3 status, Dr. Besse reported.
The majority of responses are ongoing (greater than 61% in TC3 or IC3).
Six-month overall survival rates were 82% in cohort 1, 76% in cohort 2, and 71% in cohort 3, and 79%, 80%, and 75%, respectively, in patients with TC3 or IC3 status.
The overall survival data are not yet mature after a median follow-up of 8.8 months, but the 6-month survival rates are consistent with results in POPLAR for the patients with two or three prior lines of therapy, he said.
Treatment-related grade 3/4 events occurred in 11% of 659 evaluable patients, with 5% of patients stopping atezolizumab due to an adverse event.
The safety profile is consistent with previous atezolizumab monotherapy trials, with no unexpected signals or differences in toxicity across cohorts, Dr. Besse said.
POPLAR took a different tack, evaluating the same dose of atezolizumab vs. docetaxel 75 mg/m2 IV every 3 weeks until disease progression, but in all-comers with metastatic or locally advanced NSCLC (second or third-line) who had progressed on a prior platinum therapy. The 287 patients were stratified by PD-L1 IC expression, histology, and number of prior chemotherapy regimens. In all, 16% of patients were TC3 or IC3.
The survival signal with atezolizumab was less impressive when seen at this year’s American Society of Clinical Oncology (ASCO) meeting, but with three additional months’ follow-up it now significantly favored immunotherapy over docetaxel in an intent-to-treat analysis (median 12.6 months vs. 9.7 months; hazard ratio, 0.73; P = .040).
“We have a minimum follow-up of 13 months, which means this part of the curve is less stable at the present time, but nonetheless the picture emerges that there will be ongoing separation of the curve,” study author Dr. Johan Vansteenkiste of University Hospitals KU Leuven, Belgium, said during the same immunotherapy session.
When the analysis was stratified by PD-L1 expression, the hazard ratios were 0.49 for the TC3 or IC3 patients with very high PD-L1 expression, 0.54 for TC2/3 or IC2/3 patients, 0.59 for TC1/2/3 or IC1/2/3 patients, and 1.04 for those without any PD-L1 expression.
“So there is a kind of a gradient of increasing benefit according to increased expression of PD-L1,” he said, adding that the same phenomenon was present for progression-free survival, with perhaps an even steeper gradient of increasing benefit according to intensity of staining.
The overall survival benefit was also observed in patients with squamous (HR, 0.80) and nonsquamous (HR, 0.69) histology.
The overall response rate was 15% for atezolizumab and docetaxel in the ITT analysis. Overall response differed in the subgroup with very high PD-L1 expression at 38% vs. 13%, respectively, but not in the other PD-L1 subgroups, Dr. Vansteenkiste said.
The median duration of response was 14.3 months with atezolizumab and 7.2 months with docetaxel (HR, 0.41; P = .033), with most responses ongoing, he said.
Invited discussant for both studies, Dr. Luis Paz-Ares of Hospital Universitario Virgen del Rocio in Seville, Spain, said the POPLAR overall survival results align very closely with those he reported at ASCO in the phase III CheckMate 057 study for nivolumab vs. docetaxel (median OS 12.2 months vs. 9.4 months).
“One trial actually confirms to the other, even though we are talking about two different agents from the same class and in different scenarios – phase II and phase III,” he said.
Although somewhat immature, the survival results from BIRCH are consistent with POPLAR and other phase II trials with other agents of this class, Dr. Paz-Ares said. What is yet to be determined is whether first-line patients benefit more from immunotherapy, possibly because the immune system is stronger at that point.
Dr. Martin Reck of Hospital Grosshansdorf, Germany, said atezolizumab is set to substantially change treatment strategies for patients with refractory lung cancer.
“In particular, the option for long-lasting responses and stabilization in combination with an attractive tolerability profile will impact clinical practice,” he said in a statement. “Whether patients should be selected using a biomarker strategy still needs to be determined and remains a significant challenge based on the multiple different companion diagnostics that are in use for the particular agents.”
On Twitter @pwendl
AT EUROPEAN CANCER CONGRESS 2015
Key clinical point: Atezolizumab is clinically active in advanced lung cancer and higher PD-L1 expression correlated with improved response and survival.
Major finding: Atezolizumab elicited responses in 17%-27% of patients selected for PD-L1 expression in BIRCH and significantly improved overall survival vs. docetaxel in unselected patients in POPLAR.
Data source: Two phase II trials in patients with advanced lung cancer.
Disclosures: Genentech funded both trials. Several coauthors in both studies are Genentech employees.
VIDEO: Long-term responses possible in advanced kidney cancer?
VIENNA – The survival benefit shown by nivolumab in the phase III CheckMate 025 trial may offer hope of even longer survival benefits in advanced kidney cancer.
During a press briefing at the European Cancer Congress, study author Dr. Padmanee Sharma of the University of Texas MD Anderson Cancer Center in Houston, defended immune checkpoint inhibitor nivolumab’s 5.6-month gain in overall survival.
“The immune checkpoint therapy agents are targeting your immune system,” Dr. Sharma explained in an interview. “Your immune system has the capability of giving you a memory response.” That could lead to long-term, durable responses in cancer patients that can last for years, she noted.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
VIENNA – The survival benefit shown by nivolumab in the phase III CheckMate 025 trial may offer hope of even longer survival benefits in advanced kidney cancer.
During a press briefing at the European Cancer Congress, study author Dr. Padmanee Sharma of the University of Texas MD Anderson Cancer Center in Houston, defended immune checkpoint inhibitor nivolumab’s 5.6-month gain in overall survival.
“The immune checkpoint therapy agents are targeting your immune system,” Dr. Sharma explained in an interview. “Your immune system has the capability of giving you a memory response.” That could lead to long-term, durable responses in cancer patients that can last for years, she noted.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
VIENNA – The survival benefit shown by nivolumab in the phase III CheckMate 025 trial may offer hope of even longer survival benefits in advanced kidney cancer.
During a press briefing at the European Cancer Congress, study author Dr. Padmanee Sharma of the University of Texas MD Anderson Cancer Center in Houston, defended immune checkpoint inhibitor nivolumab’s 5.6-month gain in overall survival.
“The immune checkpoint therapy agents are targeting your immune system,” Dr. Sharma explained in an interview. “Your immune system has the capability of giving you a memory response.” That could lead to long-term, durable responses in cancer patients that can last for years, she noted.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
AT THE EUROPEAN CANCER CONGRESS
