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Gene panel identifies residual neuroblastoma metastases
BRUSSELS – In advanced-stage neuroblastoma patients with residual metastases in their bone marrow following two cycles of anti-GD2 immunotherapy, another cycle of this treatment is futile and only causes adverse events, based on a review of 343 stage IV patients treated at one U.S. center.
"Bone marrow minimal residual disease [MRD] measured after two cycles of immunotherapy was the strongest predictor of outcome, irrespective of disease status at the start of immunotherapy," Dr. Nai-Kong V. Cheung said at the Markers in Cancer meeting. "If a patient is positive for MRD after two cycles, don’t continue the treatment."
In the series of 343 patients aged 18 months or older with metastatic, stage IV neuroblastoma that he reviewed, all patients with detectable MRD after two cycles of immunotherapy with GD2 antibody eventually relapsed or died within the next 5 years. In contrast, roughly half of the patients who lacked MRD after the first two cycles of anti-GD2 therapy remained progression free and alive during up to 20 years of follow-up.
The full course of anti-GD2 treatment takes 2 years, has the potential to cause adverse effects, and is painful and expensive. "Why continue and subject patients to a treatment that won’t be beneficial?" Dr. Cheung asked during an interview. "We can use [MRD] as a marker to take patients off of a protocol that will not be useful to them and try a different treatment."
Immunotherapy with anti-GD2 is part of standard treatment for patients with advanced neuroblastoma.
Dr. Cheung, a pediatric oncologist and head of the neuroblastoma program at Memorial Sloan-Kettering Cancer Center in New York, and his associates used a four-marker genetic analysis to find evidence of residual, metastatic neuroblastoma cells in patients’ bone marrow. The four markers they used were:
• GD2 synthase, the gene for an enzyme that helps produce a ganglioside-abundant in neuroblastoma cells;
• PHOX2B, the gene for a transcription factor that promotes nerve cell growth and maturation;
• CCND1, the gene for cyclin D1 protein, an oncogene; and
• ISL 1, the gene for islet 1, a transcription factor involved in cell growth.
The database included 169 patients treated during first remission, 69 treated during second or later remission, and 105 with primary refractory disease. The researchers used the four-test genetic panel to screen for MRD in bone marrow specimens taken from these patients after the first two rounds of anti-GD2 treatment with or without granulocyte-macrophage colony-stimulating factor in a series of four treatment protocols. A patient was considered positive for MRD if at least one of the genetic markers was positive for the presence of neuroblastoma cells in the bone marrow.
In a multivariate analysis, patients negative for MRD had about a fourfold increased rate of progression-free survival and about a threefold increased rate of overall survival, compared with patients positive for MRD; both differences were statistically significant.
Dr. Cheung said that the four-gene panel his group used was developed through a project begun 15 years ago to look for the most discriminating gene signatures of metastatic neuroblastoma cells against the background of normal bone marrow cells, the metastatic destination for at least 90% of advanced neuroblastoma tumors. A similar approach could identify genetic tests for treatment response of other metastatic tumor types, he said.
The meeting was sponsored by the American Society of Clinical Oncology, the European Organisation for Research and Treatment of Cancer, and the National Cancer Institute. Dr. Cheung said that he is a coinventor on patents held by Memorial Sloan-Kettering Cancer Center.
On Twitter @mitchelzoler
BRUSSELS – In advanced-stage neuroblastoma patients with residual metastases in their bone marrow following two cycles of anti-GD2 immunotherapy, another cycle of this treatment is futile and only causes adverse events, based on a review of 343 stage IV patients treated at one U.S. center.
"Bone marrow minimal residual disease [MRD] measured after two cycles of immunotherapy was the strongest predictor of outcome, irrespective of disease status at the start of immunotherapy," Dr. Nai-Kong V. Cheung said at the Markers in Cancer meeting. "If a patient is positive for MRD after two cycles, don’t continue the treatment."
In the series of 343 patients aged 18 months or older with metastatic, stage IV neuroblastoma that he reviewed, all patients with detectable MRD after two cycles of immunotherapy with GD2 antibody eventually relapsed or died within the next 5 years. In contrast, roughly half of the patients who lacked MRD after the first two cycles of anti-GD2 therapy remained progression free and alive during up to 20 years of follow-up.
The full course of anti-GD2 treatment takes 2 years, has the potential to cause adverse effects, and is painful and expensive. "Why continue and subject patients to a treatment that won’t be beneficial?" Dr. Cheung asked during an interview. "We can use [MRD] as a marker to take patients off of a protocol that will not be useful to them and try a different treatment."
Immunotherapy with anti-GD2 is part of standard treatment for patients with advanced neuroblastoma.
Dr. Cheung, a pediatric oncologist and head of the neuroblastoma program at Memorial Sloan-Kettering Cancer Center in New York, and his associates used a four-marker genetic analysis to find evidence of residual, metastatic neuroblastoma cells in patients’ bone marrow. The four markers they used were:
• GD2 synthase, the gene for an enzyme that helps produce a ganglioside-abundant in neuroblastoma cells;
• PHOX2B, the gene for a transcription factor that promotes nerve cell growth and maturation;
• CCND1, the gene for cyclin D1 protein, an oncogene; and
• ISL 1, the gene for islet 1, a transcription factor involved in cell growth.
The database included 169 patients treated during first remission, 69 treated during second or later remission, and 105 with primary refractory disease. The researchers used the four-test genetic panel to screen for MRD in bone marrow specimens taken from these patients after the first two rounds of anti-GD2 treatment with or without granulocyte-macrophage colony-stimulating factor in a series of four treatment protocols. A patient was considered positive for MRD if at least one of the genetic markers was positive for the presence of neuroblastoma cells in the bone marrow.
In a multivariate analysis, patients negative for MRD had about a fourfold increased rate of progression-free survival and about a threefold increased rate of overall survival, compared with patients positive for MRD; both differences were statistically significant.
Dr. Cheung said that the four-gene panel his group used was developed through a project begun 15 years ago to look for the most discriminating gene signatures of metastatic neuroblastoma cells against the background of normal bone marrow cells, the metastatic destination for at least 90% of advanced neuroblastoma tumors. A similar approach could identify genetic tests for treatment response of other metastatic tumor types, he said.
The meeting was sponsored by the American Society of Clinical Oncology, the European Organisation for Research and Treatment of Cancer, and the National Cancer Institute. Dr. Cheung said that he is a coinventor on patents held by Memorial Sloan-Kettering Cancer Center.
On Twitter @mitchelzoler
BRUSSELS – In advanced-stage neuroblastoma patients with residual metastases in their bone marrow following two cycles of anti-GD2 immunotherapy, another cycle of this treatment is futile and only causes adverse events, based on a review of 343 stage IV patients treated at one U.S. center.
"Bone marrow minimal residual disease [MRD] measured after two cycles of immunotherapy was the strongest predictor of outcome, irrespective of disease status at the start of immunotherapy," Dr. Nai-Kong V. Cheung said at the Markers in Cancer meeting. "If a patient is positive for MRD after two cycles, don’t continue the treatment."
In the series of 343 patients aged 18 months or older with metastatic, stage IV neuroblastoma that he reviewed, all patients with detectable MRD after two cycles of immunotherapy with GD2 antibody eventually relapsed or died within the next 5 years. In contrast, roughly half of the patients who lacked MRD after the first two cycles of anti-GD2 therapy remained progression free and alive during up to 20 years of follow-up.
The full course of anti-GD2 treatment takes 2 years, has the potential to cause adverse effects, and is painful and expensive. "Why continue and subject patients to a treatment that won’t be beneficial?" Dr. Cheung asked during an interview. "We can use [MRD] as a marker to take patients off of a protocol that will not be useful to them and try a different treatment."
Immunotherapy with anti-GD2 is part of standard treatment for patients with advanced neuroblastoma.
Dr. Cheung, a pediatric oncologist and head of the neuroblastoma program at Memorial Sloan-Kettering Cancer Center in New York, and his associates used a four-marker genetic analysis to find evidence of residual, metastatic neuroblastoma cells in patients’ bone marrow. The four markers they used were:
• GD2 synthase, the gene for an enzyme that helps produce a ganglioside-abundant in neuroblastoma cells;
• PHOX2B, the gene for a transcription factor that promotes nerve cell growth and maturation;
• CCND1, the gene for cyclin D1 protein, an oncogene; and
• ISL 1, the gene for islet 1, a transcription factor involved in cell growth.
The database included 169 patients treated during first remission, 69 treated during second or later remission, and 105 with primary refractory disease. The researchers used the four-test genetic panel to screen for MRD in bone marrow specimens taken from these patients after the first two rounds of anti-GD2 treatment with or without granulocyte-macrophage colony-stimulating factor in a series of four treatment protocols. A patient was considered positive for MRD if at least one of the genetic markers was positive for the presence of neuroblastoma cells in the bone marrow.
In a multivariate analysis, patients negative for MRD had about a fourfold increased rate of progression-free survival and about a threefold increased rate of overall survival, compared with patients positive for MRD; both differences were statistically significant.
Dr. Cheung said that the four-gene panel his group used was developed through a project begun 15 years ago to look for the most discriminating gene signatures of metastatic neuroblastoma cells against the background of normal bone marrow cells, the metastatic destination for at least 90% of advanced neuroblastoma tumors. A similar approach could identify genetic tests for treatment response of other metastatic tumor types, he said.
The meeting was sponsored by the American Society of Clinical Oncology, the European Organisation for Research and Treatment of Cancer, and the National Cancer Institute. Dr. Cheung said that he is a coinventor on patents held by Memorial Sloan-Kettering Cancer Center.
On Twitter @mitchelzoler
AT THE MARKERS IN CANCER MEETING
Major finding: In a multivariate analysis, patients negative for minimal residual disease had about a fourfold increased rate of progression-free survival and about a threefold increased rate of overall survival, compared with patients positive for MRD; both differences were statistically significant.
Data source: A review of 343 patients with stage IV neuroblastoma treated with immunotherapy at one U.S. center.
Disclosures: Dr. Cheung said that he is a coinventor on patents held by Memorial Sloan-Kettering Cancer Center.
CENTRIC results signal end of cilenglitide in glioblastoma
AMSTERDAM – The investigational drug cilenglitide failed to improve overall or progression-free survival when added to standard treatment in patients with newly diagnosed glioblastoma.
Overall survival, the primary endpoint of the CENTRIC study, was 26.3 months in both study arms, with more events occurring in the cilenglitide arm than in the control arm (144 vs. 138; hazard ratio, 1.021; P = .86). "We could not identify any subgroup that actually had a benefit from the addition of cilenglitide," said study investigator Dr. Roger Stupp at the multidisciplinary European cancer congresses.
Progression-free survival, according to independent review, was also disappointing, at 10.6 months for the cilenglitide group and 7.9 months for the control group (HR, 0.918; P = .41), reported Dr. Stupp of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
These findings signal the end of the line for the drug’s development against this tumor, Dr. Stupp remarked in presenting the results of the large phase III study. "I’m not sure we are at the end of targeting integrins, but we have taken a blow with this strategy," he said.
CENTRIC was performed in 545 patients with newly diagnosed disease and a methylated promoter of the O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene.
The median age of enrolled patients was 58 years, with 23% aged 65 years or older. A total of 272 patients were randomized to receive cilenglitide in addition to standard chemoradiotherapy and 272 to chemoradiotherapy alone. Cilenglitide was given at an infused IV dose of 2,000 mg twice weekly. Standard chemoradiotherapy consisted of 75 mg/m2 of temozolomide (TMZ), and radiotherapy consisted of a dose of 30 grays in 2-gray fractions, with maintenance TMZ (150-200 mg/m2 for six cycles).
Another trial whose results were presented was the phase II CORE trial, which enrolled 265 patients with newly diagnosed glioblastoma and unmethylated MGMT. Patients were randomized into three groups: a control arm of standard chemotherapy of TMZ plus radiotherapy, and then maintenance TMZ (n = 89); a standard cilenglitide dosing arm, with patients receiving 2,000 mg twice a week in addition to chemoradiotherapy (n = 88); and an intensive dosing arm, with the dose of cilenglitide upped to 2,000 mg five times a week in addition to chemoradiotherapy (n = 88).
Contrary to the CENTRIC study results, the CORE study findings suggested there was a benefit of adding cilenglitide to standard therapy. Median overall survival was 13.4 months in the control arm, but 16.3 months in the standard cilenglitide dosing arm (hazard ratio, 0.69 vs. control). Median overall survival in the intensive treatment arm was 14.5 months (HR, 0.86 vs. control).
Investigator-assessed progression-free survival also suggested a benefit of adding cilenglitide.
"These findings are inconsistent with the larger, phase III CENTRIC clinical trial," said Dr. L. Burt Nabors of the University of Alabama at Birmingham, who presented the CORE findings. "This is a limited study. It was more exploratory in nature, with a sample size that was obviously smaller." He suggested that further investigations are required to look at possible biomarkers.
Commenting on the CENTRIC study, Dr. Michael Brada of University College Hospital, London, observed: "It’s been a bumpy year for randomized trials." Recent trials in glioblastoma have generally been disappointing, and the CENTRIC study results now add to the negative results.
Additional phase I/II trials are investigating the potential of cilenglitide in combination with radiotherapy and chemotherapy in patients with locally advanced non–small cell lung cancer (NCT01118676), and in combination with chemotherapy in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (NCT00705016).
The CENTRIC and CORE studies were sponsored by Merck. Dr. Stupp has received honoraria for consultancy work from Merck Serono, MSD-Merck, and Roche/Genentech. Dr. Nabors had no conflicts of interest to disclose. Dr. Brada has participated on advisory boards for Roche and Merck.
AMSTERDAM – The investigational drug cilenglitide failed to improve overall or progression-free survival when added to standard treatment in patients with newly diagnosed glioblastoma.
Overall survival, the primary endpoint of the CENTRIC study, was 26.3 months in both study arms, with more events occurring in the cilenglitide arm than in the control arm (144 vs. 138; hazard ratio, 1.021; P = .86). "We could not identify any subgroup that actually had a benefit from the addition of cilenglitide," said study investigator Dr. Roger Stupp at the multidisciplinary European cancer congresses.
Progression-free survival, according to independent review, was also disappointing, at 10.6 months for the cilenglitide group and 7.9 months for the control group (HR, 0.918; P = .41), reported Dr. Stupp of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
These findings signal the end of the line for the drug’s development against this tumor, Dr. Stupp remarked in presenting the results of the large phase III study. "I’m not sure we are at the end of targeting integrins, but we have taken a blow with this strategy," he said.
CENTRIC was performed in 545 patients with newly diagnosed disease and a methylated promoter of the O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene.
The median age of enrolled patients was 58 years, with 23% aged 65 years or older. A total of 272 patients were randomized to receive cilenglitide in addition to standard chemoradiotherapy and 272 to chemoradiotherapy alone. Cilenglitide was given at an infused IV dose of 2,000 mg twice weekly. Standard chemoradiotherapy consisted of 75 mg/m2 of temozolomide (TMZ), and radiotherapy consisted of a dose of 30 grays in 2-gray fractions, with maintenance TMZ (150-200 mg/m2 for six cycles).
Another trial whose results were presented was the phase II CORE trial, which enrolled 265 patients with newly diagnosed glioblastoma and unmethylated MGMT. Patients were randomized into three groups: a control arm of standard chemotherapy of TMZ plus radiotherapy, and then maintenance TMZ (n = 89); a standard cilenglitide dosing arm, with patients receiving 2,000 mg twice a week in addition to chemoradiotherapy (n = 88); and an intensive dosing arm, with the dose of cilenglitide upped to 2,000 mg five times a week in addition to chemoradiotherapy (n = 88).
Contrary to the CENTRIC study results, the CORE study findings suggested there was a benefit of adding cilenglitide to standard therapy. Median overall survival was 13.4 months in the control arm, but 16.3 months in the standard cilenglitide dosing arm (hazard ratio, 0.69 vs. control). Median overall survival in the intensive treatment arm was 14.5 months (HR, 0.86 vs. control).
Investigator-assessed progression-free survival also suggested a benefit of adding cilenglitide.
"These findings are inconsistent with the larger, phase III CENTRIC clinical trial," said Dr. L. Burt Nabors of the University of Alabama at Birmingham, who presented the CORE findings. "This is a limited study. It was more exploratory in nature, with a sample size that was obviously smaller." He suggested that further investigations are required to look at possible biomarkers.
Commenting on the CENTRIC study, Dr. Michael Brada of University College Hospital, London, observed: "It’s been a bumpy year for randomized trials." Recent trials in glioblastoma have generally been disappointing, and the CENTRIC study results now add to the negative results.
Additional phase I/II trials are investigating the potential of cilenglitide in combination with radiotherapy and chemotherapy in patients with locally advanced non–small cell lung cancer (NCT01118676), and in combination with chemotherapy in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (NCT00705016).
The CENTRIC and CORE studies were sponsored by Merck. Dr. Stupp has received honoraria for consultancy work from Merck Serono, MSD-Merck, and Roche/Genentech. Dr. Nabors had no conflicts of interest to disclose. Dr. Brada has participated on advisory boards for Roche and Merck.
AMSTERDAM – The investigational drug cilenglitide failed to improve overall or progression-free survival when added to standard treatment in patients with newly diagnosed glioblastoma.
Overall survival, the primary endpoint of the CENTRIC study, was 26.3 months in both study arms, with more events occurring in the cilenglitide arm than in the control arm (144 vs. 138; hazard ratio, 1.021; P = .86). "We could not identify any subgroup that actually had a benefit from the addition of cilenglitide," said study investigator Dr. Roger Stupp at the multidisciplinary European cancer congresses.
Progression-free survival, according to independent review, was also disappointing, at 10.6 months for the cilenglitide group and 7.9 months for the control group (HR, 0.918; P = .41), reported Dr. Stupp of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
These findings signal the end of the line for the drug’s development against this tumor, Dr. Stupp remarked in presenting the results of the large phase III study. "I’m not sure we are at the end of targeting integrins, but we have taken a blow with this strategy," he said.
CENTRIC was performed in 545 patients with newly diagnosed disease and a methylated promoter of the O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene.
The median age of enrolled patients was 58 years, with 23% aged 65 years or older. A total of 272 patients were randomized to receive cilenglitide in addition to standard chemoradiotherapy and 272 to chemoradiotherapy alone. Cilenglitide was given at an infused IV dose of 2,000 mg twice weekly. Standard chemoradiotherapy consisted of 75 mg/m2 of temozolomide (TMZ), and radiotherapy consisted of a dose of 30 grays in 2-gray fractions, with maintenance TMZ (150-200 mg/m2 for six cycles).
Another trial whose results were presented was the phase II CORE trial, which enrolled 265 patients with newly diagnosed glioblastoma and unmethylated MGMT. Patients were randomized into three groups: a control arm of standard chemotherapy of TMZ plus radiotherapy, and then maintenance TMZ (n = 89); a standard cilenglitide dosing arm, with patients receiving 2,000 mg twice a week in addition to chemoradiotherapy (n = 88); and an intensive dosing arm, with the dose of cilenglitide upped to 2,000 mg five times a week in addition to chemoradiotherapy (n = 88).
Contrary to the CENTRIC study results, the CORE study findings suggested there was a benefit of adding cilenglitide to standard therapy. Median overall survival was 13.4 months in the control arm, but 16.3 months in the standard cilenglitide dosing arm (hazard ratio, 0.69 vs. control). Median overall survival in the intensive treatment arm was 14.5 months (HR, 0.86 vs. control).
Investigator-assessed progression-free survival also suggested a benefit of adding cilenglitide.
"These findings are inconsistent with the larger, phase III CENTRIC clinical trial," said Dr. L. Burt Nabors of the University of Alabama at Birmingham, who presented the CORE findings. "This is a limited study. It was more exploratory in nature, with a sample size that was obviously smaller." He suggested that further investigations are required to look at possible biomarkers.
Commenting on the CENTRIC study, Dr. Michael Brada of University College Hospital, London, observed: "It’s been a bumpy year for randomized trials." Recent trials in glioblastoma have generally been disappointing, and the CENTRIC study results now add to the negative results.
Additional phase I/II trials are investigating the potential of cilenglitide in combination with radiotherapy and chemotherapy in patients with locally advanced non–small cell lung cancer (NCT01118676), and in combination with chemotherapy in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (NCT00705016).
The CENTRIC and CORE studies were sponsored by Merck. Dr. Stupp has received honoraria for consultancy work from Merck Serono, MSD-Merck, and Roche/Genentech. Dr. Nabors had no conflicts of interest to disclose. Dr. Brada has participated on advisory boards for Roche and Merck.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: Overall survival was 26.3 months in both study arms, and more events occurred in the cilenglitide arm than in the control arm (144 vs. 138; hazard ratio, 1.021; P = .86).
Data source: Two multicenter, randomized trials of newly diagnosed glioblastoma patients: CENTRIC, a double-blind phase III study of 545 glioblastoma patients treated with standard chemoradiotherapy with or without additional cilenglitide; and CORE, an open-label phase II study of standard or intensively dosed cilenglitide added to standard chemoradiotherapy.
Disclosures: The CENTRIC and CORE studies were sponsored by Merck. Dr. Stupp has received honoraria for consultancy work from Merck Serono, MSD-Merck, and Roche/Genentech. Dr. Nabors had no conflicts of interest to disclose. Dr. Brada has participated on advisory boards for Roche and Merck.
Younger adults with brain metastases survive longer with radiosurgery alone
ATLANTA – Younger adults with one to three brain metastases survive longer when they are treated with stereotactic radiosurgery alone rather than whole-brain radiation therapy or a combination of both modalities, researchers reported at the annual meeting of the American Society for Radiation Oncology.
Among patients aged 35-50 years, stereotactic radiosurgery (SRS) alone was associated with hazard ratios (HR) for death ranging from 0.46 to 0.64, compared with an age-matched cohort treated with a combination of SRS and whole-brain radiation therapy (WBRT), based on a meta-analysis of data on 389 individual patients in three randomized clinical trials.
For local control, however, the data show a benefit for combined SRS and WBRT. For control of distant brain metastases, the data indicate a benefit for the combined therapies, but only among patients aged 55 years and older, reported Dr. Arjun Sahgal, associate professor of radiation oncology at the University of Toronto.
"Our overall survival results favoring radiosurgery alone in younger patients may be explained by the lack of benefit of whole-brain radiation with respect to distant brain control in this cohort, while still exposing them to the harms of whole-brain radiation with respect to memory function and quality of life," he said.
Dr. Sahgal and his colleagues had previously published an aggregate meta-analysis showing that WBRT and SRS improved distant and local brain control but without overall survival benefit compared with SRS alone.
The current study looked at the raw, individual patient data from the three randomized controlled trials included in the original aggregate analysis. The trials included a 2006 study of 132 patients with an endpoint of brain tumor recurrence, a 2009 trial looking at the effect of SRS/WBRT on neurocognitive function in 58 patients, and a 2011 study examining the effect of adjuvant SRS on World Health Organization performance status scores.
The overall median time to local failure in the trials was 6.6 months for SRS alone, compared with 7.7 months for SRS/WBRT. Time to distant failure was also shorter with SRS alone, at a median of 4.7 vs. 7.7 months, respectively. Median time to death, however, was longer with SRS, at 10 vs. 8.2 months.
In a multivariate model for overall survival, the HR was 0.46 for patients at age 35 years, 0.52 at age 40, 0.58 at age 45, and 0.64 at age 50; all hazard ratios had significant confidence intervals. For patients aged 55 years and older, however, the HR for overall survival was not significant.
Patients with only one metastasis had a significantly lower risk of dying, compared with those who had two or three metastases (HR, 0.72).
The risk of local failure was significantly greater with SRS alone for patients aged 45-70.
The risk of new distant metastases was significant with SRS alone for patients aged 55 years and older, and was significantly lower for patients with one metastasis (HR, 0.63) vs. two or more metastases.
Salvage therapy was performed in 28% of patients who underwent SRS alone and 12% of those who received the combined therapies. Distant brain failures occurred in 54% of those in the SRS alone group, compared with 34% of those in the SRS/WBRT group.
Patients who underwent salvage therapy had significantly greater survival rates than those who did not, and this effect did not vary significantly by age, Dr. Sahgal reported.
The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.
ATLANTA – Younger adults with one to three brain metastases survive longer when they are treated with stereotactic radiosurgery alone rather than whole-brain radiation therapy or a combination of both modalities, researchers reported at the annual meeting of the American Society for Radiation Oncology.
Among patients aged 35-50 years, stereotactic radiosurgery (SRS) alone was associated with hazard ratios (HR) for death ranging from 0.46 to 0.64, compared with an age-matched cohort treated with a combination of SRS and whole-brain radiation therapy (WBRT), based on a meta-analysis of data on 389 individual patients in three randomized clinical trials.
For local control, however, the data show a benefit for combined SRS and WBRT. For control of distant brain metastases, the data indicate a benefit for the combined therapies, but only among patients aged 55 years and older, reported Dr. Arjun Sahgal, associate professor of radiation oncology at the University of Toronto.
"Our overall survival results favoring radiosurgery alone in younger patients may be explained by the lack of benefit of whole-brain radiation with respect to distant brain control in this cohort, while still exposing them to the harms of whole-brain radiation with respect to memory function and quality of life," he said.
Dr. Sahgal and his colleagues had previously published an aggregate meta-analysis showing that WBRT and SRS improved distant and local brain control but without overall survival benefit compared with SRS alone.
The current study looked at the raw, individual patient data from the three randomized controlled trials included in the original aggregate analysis. The trials included a 2006 study of 132 patients with an endpoint of brain tumor recurrence, a 2009 trial looking at the effect of SRS/WBRT on neurocognitive function in 58 patients, and a 2011 study examining the effect of adjuvant SRS on World Health Organization performance status scores.
The overall median time to local failure in the trials was 6.6 months for SRS alone, compared with 7.7 months for SRS/WBRT. Time to distant failure was also shorter with SRS alone, at a median of 4.7 vs. 7.7 months, respectively. Median time to death, however, was longer with SRS, at 10 vs. 8.2 months.
In a multivariate model for overall survival, the HR was 0.46 for patients at age 35 years, 0.52 at age 40, 0.58 at age 45, and 0.64 at age 50; all hazard ratios had significant confidence intervals. For patients aged 55 years and older, however, the HR for overall survival was not significant.
Patients with only one metastasis had a significantly lower risk of dying, compared with those who had two or three metastases (HR, 0.72).
The risk of local failure was significantly greater with SRS alone for patients aged 45-70.
The risk of new distant metastases was significant with SRS alone for patients aged 55 years and older, and was significantly lower for patients with one metastasis (HR, 0.63) vs. two or more metastases.
Salvage therapy was performed in 28% of patients who underwent SRS alone and 12% of those who received the combined therapies. Distant brain failures occurred in 54% of those in the SRS alone group, compared with 34% of those in the SRS/WBRT group.
Patients who underwent salvage therapy had significantly greater survival rates than those who did not, and this effect did not vary significantly by age, Dr. Sahgal reported.
The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.
ATLANTA – Younger adults with one to three brain metastases survive longer when they are treated with stereotactic radiosurgery alone rather than whole-brain radiation therapy or a combination of both modalities, researchers reported at the annual meeting of the American Society for Radiation Oncology.
Among patients aged 35-50 years, stereotactic radiosurgery (SRS) alone was associated with hazard ratios (HR) for death ranging from 0.46 to 0.64, compared with an age-matched cohort treated with a combination of SRS and whole-brain radiation therapy (WBRT), based on a meta-analysis of data on 389 individual patients in three randomized clinical trials.
For local control, however, the data show a benefit for combined SRS and WBRT. For control of distant brain metastases, the data indicate a benefit for the combined therapies, but only among patients aged 55 years and older, reported Dr. Arjun Sahgal, associate professor of radiation oncology at the University of Toronto.
"Our overall survival results favoring radiosurgery alone in younger patients may be explained by the lack of benefit of whole-brain radiation with respect to distant brain control in this cohort, while still exposing them to the harms of whole-brain radiation with respect to memory function and quality of life," he said.
Dr. Sahgal and his colleagues had previously published an aggregate meta-analysis showing that WBRT and SRS improved distant and local brain control but without overall survival benefit compared with SRS alone.
The current study looked at the raw, individual patient data from the three randomized controlled trials included in the original aggregate analysis. The trials included a 2006 study of 132 patients with an endpoint of brain tumor recurrence, a 2009 trial looking at the effect of SRS/WBRT on neurocognitive function in 58 patients, and a 2011 study examining the effect of adjuvant SRS on World Health Organization performance status scores.
The overall median time to local failure in the trials was 6.6 months for SRS alone, compared with 7.7 months for SRS/WBRT. Time to distant failure was also shorter with SRS alone, at a median of 4.7 vs. 7.7 months, respectively. Median time to death, however, was longer with SRS, at 10 vs. 8.2 months.
In a multivariate model for overall survival, the HR was 0.46 for patients at age 35 years, 0.52 at age 40, 0.58 at age 45, and 0.64 at age 50; all hazard ratios had significant confidence intervals. For patients aged 55 years and older, however, the HR for overall survival was not significant.
Patients with only one metastasis had a significantly lower risk of dying, compared with those who had two or three metastases (HR, 0.72).
The risk of local failure was significantly greater with SRS alone for patients aged 45-70.
The risk of new distant metastases was significant with SRS alone for patients aged 55 years and older, and was significantly lower for patients with one metastasis (HR, 0.63) vs. two or more metastases.
Salvage therapy was performed in 28% of patients who underwent SRS alone and 12% of those who received the combined therapies. Distant brain failures occurred in 54% of those in the SRS alone group, compared with 34% of those in the SRS/WBRT group.
Patients who underwent salvage therapy had significantly greater survival rates than those who did not, and this effect did not vary significantly by age, Dr. Sahgal reported.
The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.
AT THE ASTRO ANNUAL MEETING
Major finding: Stereotactic radiosurgery was associated with significantly longer overall survival among patients age 50 years and younger (hazard ratios from 0.46 to 0.64).
Data source: Meta-analysis of individual patient data from three randomized controlled clinical trials enrolling a total of 389 patients.
Disclosures: The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.
Study indicates potential for longer survival after radiosurgery for brain metastases
ATLANTA – Patients with non–small cell lung cancer and fewer than four brain metastases treated with stereotactic radiosurgery had better overall survival than did similar patients treated with whole-brain irradiation in a nonrandomized observational study.
The study of 413 patients who were eligible for either treatment showed that the median overall survival was 9.0 months for those treated with stereotactic radiosurgery (SRS) alone, versus 3.9 months for those treated with whole-brain radiation therapy (WBRT) alone, reported Dr. Lia M. Halasz, assistant professor of radiation oncology at the University of Washington in Seattle.
The findings suggest the need for a randomized clinical trial comparing the two treatment strategies in patients with non–small cell lung cancer and up to three brain metastases, she said at the annual meeting of the American Society for Radiation Oncology.
"This observational data may better reflect real-world practice; however, the caveat is that all of these patients were treated at large NCCN [National Comprehensive Cancer Network] institutions, and may not reflect practices all across the United States," she said.
Dr. James B. Yu, a therapeutic radiologist and cancer outcomes researcher at Yale University, New Haven, Conn., commented that the study shows "at the very least, NCCN sites are doing a very good job at selecting patients for radiosurgery." Dr. Yu, the invited discussant, was not involved in the study.
There have been no randomized clinical trials directly comparing SRS alone vs. WBRT alone in patients with newly diagnosed brain metastases, and the optimal treatment for such patients is unknown, Dr. Halasz said. The investigators therefore undertook an observational study to determine whether one strategy had a therapeutic advantage over the other.
They identified 413 patients diagnosed with brain metastases without leptomeningeal disease from an NCCN longitudinal database from November 2006 through January 2010. The patients had all received radiation therapy with no neurosurgical resection within 60 days of diagnosis.
Of this group, 118 (29%) underwent SRS, 295 (71%) had WBRT; and 13 patients (3%) had both as initial treatment.
Patients with three or fewer metastases were significantly more likely to receive SRS than WBRT, whereas those with four or more metastases were more likely to receive WBRT (P less than .001). Other factors associated with choice of SRS were smaller metastases (P = .036) and one or no sites of extracranial disease, compared with two or more (P = .013).
The authors analyzed a subset of 197 patients with fewer than four brain metastases and all metastatic sites smaller than 4 cm, all of whom were eligible for either treatment, and 48% of whom underwent SRS alone. As noted before, the unadjusted overall survival in this group was 9.0 months for the SRS-treated patients, and 3.9 months for those treated with WBRT.
To compensate for patient-selection biases, the authors then performed a propensity score analysis in which they stratified patients by their propensity to receive radiosurgery. In this analysis, the estimated treatment effect of SRS on overall survival was a hazard ratio (HR) of 0.62 (P = .018). Factors significantly associated with overall survival included SRS vs. WBRT, number of brain metastases, extent of extracranial disease, institution, and year of treatment.
In an analysis using a standardized mortality-ratio weighing method, they found that the estimated treatment effect of SRS on overall survival was an HR of 0.67 (P = .007).
Additionally, the authors performed a sensitivity analysis of potential unmeasured confounders, assuming that patients who underwent WBRT were three times more likely to have a Karnofsky performance score less than 70, and that the HR for that poor performance status was 2.13, based on recursive partitioning analysis (RPA) status. In this analysis, the HR favoring SRS was 0.64 (P = .037).
Finally, they performed a companion analysis with breast cancer data, and found a similar HR in favor of SRS (HR, 0.59; P = .036)
The funding source for the study was not reported. Dr. Halasz and Dr. Yu reported having no conflicts of interest to disclose.
ATLANTA – Patients with non–small cell lung cancer and fewer than four brain metastases treated with stereotactic radiosurgery had better overall survival than did similar patients treated with whole-brain irradiation in a nonrandomized observational study.
The study of 413 patients who were eligible for either treatment showed that the median overall survival was 9.0 months for those treated with stereotactic radiosurgery (SRS) alone, versus 3.9 months for those treated with whole-brain radiation therapy (WBRT) alone, reported Dr. Lia M. Halasz, assistant professor of radiation oncology at the University of Washington in Seattle.
The findings suggest the need for a randomized clinical trial comparing the two treatment strategies in patients with non–small cell lung cancer and up to three brain metastases, she said at the annual meeting of the American Society for Radiation Oncology.
"This observational data may better reflect real-world practice; however, the caveat is that all of these patients were treated at large NCCN [National Comprehensive Cancer Network] institutions, and may not reflect practices all across the United States," she said.
Dr. James B. Yu, a therapeutic radiologist and cancer outcomes researcher at Yale University, New Haven, Conn., commented that the study shows "at the very least, NCCN sites are doing a very good job at selecting patients for radiosurgery." Dr. Yu, the invited discussant, was not involved in the study.
There have been no randomized clinical trials directly comparing SRS alone vs. WBRT alone in patients with newly diagnosed brain metastases, and the optimal treatment for such patients is unknown, Dr. Halasz said. The investigators therefore undertook an observational study to determine whether one strategy had a therapeutic advantage over the other.
They identified 413 patients diagnosed with brain metastases without leptomeningeal disease from an NCCN longitudinal database from November 2006 through January 2010. The patients had all received radiation therapy with no neurosurgical resection within 60 days of diagnosis.
Of this group, 118 (29%) underwent SRS, 295 (71%) had WBRT; and 13 patients (3%) had both as initial treatment.
Patients with three or fewer metastases were significantly more likely to receive SRS than WBRT, whereas those with four or more metastases were more likely to receive WBRT (P less than .001). Other factors associated with choice of SRS were smaller metastases (P = .036) and one or no sites of extracranial disease, compared with two or more (P = .013).
The authors analyzed a subset of 197 patients with fewer than four brain metastases and all metastatic sites smaller than 4 cm, all of whom were eligible for either treatment, and 48% of whom underwent SRS alone. As noted before, the unadjusted overall survival in this group was 9.0 months for the SRS-treated patients, and 3.9 months for those treated with WBRT.
To compensate for patient-selection biases, the authors then performed a propensity score analysis in which they stratified patients by their propensity to receive radiosurgery. In this analysis, the estimated treatment effect of SRS on overall survival was a hazard ratio (HR) of 0.62 (P = .018). Factors significantly associated with overall survival included SRS vs. WBRT, number of brain metastases, extent of extracranial disease, institution, and year of treatment.
In an analysis using a standardized mortality-ratio weighing method, they found that the estimated treatment effect of SRS on overall survival was an HR of 0.67 (P = .007).
Additionally, the authors performed a sensitivity analysis of potential unmeasured confounders, assuming that patients who underwent WBRT were three times more likely to have a Karnofsky performance score less than 70, and that the HR for that poor performance status was 2.13, based on recursive partitioning analysis (RPA) status. In this analysis, the HR favoring SRS was 0.64 (P = .037).
Finally, they performed a companion analysis with breast cancer data, and found a similar HR in favor of SRS (HR, 0.59; P = .036)
The funding source for the study was not reported. Dr. Halasz and Dr. Yu reported having no conflicts of interest to disclose.
ATLANTA – Patients with non–small cell lung cancer and fewer than four brain metastases treated with stereotactic radiosurgery had better overall survival than did similar patients treated with whole-brain irradiation in a nonrandomized observational study.
The study of 413 patients who were eligible for either treatment showed that the median overall survival was 9.0 months for those treated with stereotactic radiosurgery (SRS) alone, versus 3.9 months for those treated with whole-brain radiation therapy (WBRT) alone, reported Dr. Lia M. Halasz, assistant professor of radiation oncology at the University of Washington in Seattle.
The findings suggest the need for a randomized clinical trial comparing the two treatment strategies in patients with non–small cell lung cancer and up to three brain metastases, she said at the annual meeting of the American Society for Radiation Oncology.
"This observational data may better reflect real-world practice; however, the caveat is that all of these patients were treated at large NCCN [National Comprehensive Cancer Network] institutions, and may not reflect practices all across the United States," she said.
Dr. James B. Yu, a therapeutic radiologist and cancer outcomes researcher at Yale University, New Haven, Conn., commented that the study shows "at the very least, NCCN sites are doing a very good job at selecting patients for radiosurgery." Dr. Yu, the invited discussant, was not involved in the study.
There have been no randomized clinical trials directly comparing SRS alone vs. WBRT alone in patients with newly diagnosed brain metastases, and the optimal treatment for such patients is unknown, Dr. Halasz said. The investigators therefore undertook an observational study to determine whether one strategy had a therapeutic advantage over the other.
They identified 413 patients diagnosed with brain metastases without leptomeningeal disease from an NCCN longitudinal database from November 2006 through January 2010. The patients had all received radiation therapy with no neurosurgical resection within 60 days of diagnosis.
Of this group, 118 (29%) underwent SRS, 295 (71%) had WBRT; and 13 patients (3%) had both as initial treatment.
Patients with three or fewer metastases were significantly more likely to receive SRS than WBRT, whereas those with four or more metastases were more likely to receive WBRT (P less than .001). Other factors associated with choice of SRS were smaller metastases (P = .036) and one or no sites of extracranial disease, compared with two or more (P = .013).
The authors analyzed a subset of 197 patients with fewer than four brain metastases and all metastatic sites smaller than 4 cm, all of whom were eligible for either treatment, and 48% of whom underwent SRS alone. As noted before, the unadjusted overall survival in this group was 9.0 months for the SRS-treated patients, and 3.9 months for those treated with WBRT.
To compensate for patient-selection biases, the authors then performed a propensity score analysis in which they stratified patients by their propensity to receive radiosurgery. In this analysis, the estimated treatment effect of SRS on overall survival was a hazard ratio (HR) of 0.62 (P = .018). Factors significantly associated with overall survival included SRS vs. WBRT, number of brain metastases, extent of extracranial disease, institution, and year of treatment.
In an analysis using a standardized mortality-ratio weighing method, they found that the estimated treatment effect of SRS on overall survival was an HR of 0.67 (P = .007).
Additionally, the authors performed a sensitivity analysis of potential unmeasured confounders, assuming that patients who underwent WBRT were three times more likely to have a Karnofsky performance score less than 70, and that the HR for that poor performance status was 2.13, based on recursive partitioning analysis (RPA) status. In this analysis, the HR favoring SRS was 0.64 (P = .037).
Finally, they performed a companion analysis with breast cancer data, and found a similar HR in favor of SRS (HR, 0.59; P = .036)
The funding source for the study was not reported. Dr. Halasz and Dr. Yu reported having no conflicts of interest to disclose.
AT THE ASTRO ANNUAL MEETING
Major finding: Median overall survival for patients with brain metastases from non–small cell lung cancer was 9.0 months for those treated with stereotactic radiosurgery, versus 3.9 months for those treated with whole-brain radiation therapy.
Data source: Observational study of 413 patients in a National Comprehensive Cancer Network database.
Disclosures: The funding source for the study was not reported. Dr. Halasz and Dr. Yu reported having no conflicts of interest to disclose.
Spare the hippocampus, preserve the memory in whole brain irradiation
ATLANTA – Sparing the hippocampus during whole brain irradiation can pay off in memory preservation for months to come, according to Dr. Vinai Gondi.
Adults with brain metastases who underwent whole brain radiation therapy (WBRT) with a conformal technique designed to minimize radiation dose to the hippocampus had a significantly smaller mean decline in verbal memory 4 months after treatment than did historical controls, reported Dr. Gondi, codirector of the Cadence Health Brain Tumor Center in Chicago and a coprincipal investigator in the Radiation Therapy Oncology Group Trial 0933.
"These phase II results are promising, and highlight the importance of the hippocampus as a radiosensitive structure central to memory toxicity," Dr. Gondi said in a briefing prior to his presentation in a plenary session of the American Society for Radiation Oncology.
The hippocampus has been shown to play host to neural stem cells that are constantly differentiating into new neurons throughout adult life, a process important for maintaining memory function, he noted.
Previous studies have shown that cranial irradiation with WBRT is associated with a 4- to 6-month decline in memory function, as measured by the Hopkins Verbal Learning Test (HVLT) total recall and delayed recall items.
By using intensity modulated radiation therapy (IMRT) to shape the beam and largely spare the pocket of neural stem cells in the dentate gyrus portion of the hippocampus, the investigators hoped to avoid the decrements in memory function seen with earlier, less discriminating WBRT techniques, he said.
They enrolled 113 adults with brain metastases from various primary malignancies and assigned them to receive hippocampal-avoiding WBRT of 30 Gy delivered in 10 fractions. Radiation oncologists participating in the trial were trained in the technique, which involves careful identification of hippocampal landmarks and titration of the dose to minimize exposure of the hippocampus in general, and the dentate gyrus in particular. Under the protocol, the total radiation dose to the entire volume of the hippocampus can be no more than 10 Gy, and no single point in the hippocampus can receive more than 17 Gy.
Controls were patients in an earlier phase III clinical trial who underwent WBRT without hippocampal avoidance.
At 4 months, 100 patients treated with the hippocampal-sparing technique who were available for analysis had a 7% decline in the primary endpoint – delayed recall scores from baseline – compared with 30% for historical controls (P = .0003).
Among the 29 patients for whom 6-month data were available, the mean relative decline from baseline in delayed recall was 2% and in immediate recall was 0.7%. In contrast, there was a 3% increase in total recall scores.
The risk of metastasis to the hippocampus was 4.5% during follow-up, Dr. Gondi said.
The Radiation Oncology Therapy Group is currently developing a phase III trial of prophylactic cranial radiation with or without hippocampal avoidance for patients with small cell lung cancer.
The study demonstrates the value of improving and incorporating into practice newer radiation delivery technologies such as IMRT, said Dr. Bruce G. Haffty, a radiation oncologist at the Cancer Institute of New Jersey in New Brunswick, and ASTRO president-elect.
"It’s nice to have that technology available, and it’s now nice to see that we can use that technology to [reduce] memory loss and improve quality of life for our patients undergoing whole brain radiation therapy," he said.
Dr. Haffty moderated the briefing, but was not involved in the study.
RTOG 0993 was supported by the National Cancer Institute. Dr. Gondi and Dr. Haffty reported having no relevant financial conflicts.
ATLANTA – Sparing the hippocampus during whole brain irradiation can pay off in memory preservation for months to come, according to Dr. Vinai Gondi.
Adults with brain metastases who underwent whole brain radiation therapy (WBRT) with a conformal technique designed to minimize radiation dose to the hippocampus had a significantly smaller mean decline in verbal memory 4 months after treatment than did historical controls, reported Dr. Gondi, codirector of the Cadence Health Brain Tumor Center in Chicago and a coprincipal investigator in the Radiation Therapy Oncology Group Trial 0933.
"These phase II results are promising, and highlight the importance of the hippocampus as a radiosensitive structure central to memory toxicity," Dr. Gondi said in a briefing prior to his presentation in a plenary session of the American Society for Radiation Oncology.
The hippocampus has been shown to play host to neural stem cells that are constantly differentiating into new neurons throughout adult life, a process important for maintaining memory function, he noted.
Previous studies have shown that cranial irradiation with WBRT is associated with a 4- to 6-month decline in memory function, as measured by the Hopkins Verbal Learning Test (HVLT) total recall and delayed recall items.
By using intensity modulated radiation therapy (IMRT) to shape the beam and largely spare the pocket of neural stem cells in the dentate gyrus portion of the hippocampus, the investigators hoped to avoid the decrements in memory function seen with earlier, less discriminating WBRT techniques, he said.
They enrolled 113 adults with brain metastases from various primary malignancies and assigned them to receive hippocampal-avoiding WBRT of 30 Gy delivered in 10 fractions. Radiation oncologists participating in the trial were trained in the technique, which involves careful identification of hippocampal landmarks and titration of the dose to minimize exposure of the hippocampus in general, and the dentate gyrus in particular. Under the protocol, the total radiation dose to the entire volume of the hippocampus can be no more than 10 Gy, and no single point in the hippocampus can receive more than 17 Gy.
Controls were patients in an earlier phase III clinical trial who underwent WBRT without hippocampal avoidance.
At 4 months, 100 patients treated with the hippocampal-sparing technique who were available for analysis had a 7% decline in the primary endpoint – delayed recall scores from baseline – compared with 30% for historical controls (P = .0003).
Among the 29 patients for whom 6-month data were available, the mean relative decline from baseline in delayed recall was 2% and in immediate recall was 0.7%. In contrast, there was a 3% increase in total recall scores.
The risk of metastasis to the hippocampus was 4.5% during follow-up, Dr. Gondi said.
The Radiation Oncology Therapy Group is currently developing a phase III trial of prophylactic cranial radiation with or without hippocampal avoidance for patients with small cell lung cancer.
The study demonstrates the value of improving and incorporating into practice newer radiation delivery technologies such as IMRT, said Dr. Bruce G. Haffty, a radiation oncologist at the Cancer Institute of New Jersey in New Brunswick, and ASTRO president-elect.
"It’s nice to have that technology available, and it’s now nice to see that we can use that technology to [reduce] memory loss and improve quality of life for our patients undergoing whole brain radiation therapy," he said.
Dr. Haffty moderated the briefing, but was not involved in the study.
RTOG 0993 was supported by the National Cancer Institute. Dr. Gondi and Dr. Haffty reported having no relevant financial conflicts.
ATLANTA – Sparing the hippocampus during whole brain irradiation can pay off in memory preservation for months to come, according to Dr. Vinai Gondi.
Adults with brain metastases who underwent whole brain radiation therapy (WBRT) with a conformal technique designed to minimize radiation dose to the hippocampus had a significantly smaller mean decline in verbal memory 4 months after treatment than did historical controls, reported Dr. Gondi, codirector of the Cadence Health Brain Tumor Center in Chicago and a coprincipal investigator in the Radiation Therapy Oncology Group Trial 0933.
"These phase II results are promising, and highlight the importance of the hippocampus as a radiosensitive structure central to memory toxicity," Dr. Gondi said in a briefing prior to his presentation in a plenary session of the American Society for Radiation Oncology.
The hippocampus has been shown to play host to neural stem cells that are constantly differentiating into new neurons throughout adult life, a process important for maintaining memory function, he noted.
Previous studies have shown that cranial irradiation with WBRT is associated with a 4- to 6-month decline in memory function, as measured by the Hopkins Verbal Learning Test (HVLT) total recall and delayed recall items.
By using intensity modulated radiation therapy (IMRT) to shape the beam and largely spare the pocket of neural stem cells in the dentate gyrus portion of the hippocampus, the investigators hoped to avoid the decrements in memory function seen with earlier, less discriminating WBRT techniques, he said.
They enrolled 113 adults with brain metastases from various primary malignancies and assigned them to receive hippocampal-avoiding WBRT of 30 Gy delivered in 10 fractions. Radiation oncologists participating in the trial were trained in the technique, which involves careful identification of hippocampal landmarks and titration of the dose to minimize exposure of the hippocampus in general, and the dentate gyrus in particular. Under the protocol, the total radiation dose to the entire volume of the hippocampus can be no more than 10 Gy, and no single point in the hippocampus can receive more than 17 Gy.
Controls were patients in an earlier phase III clinical trial who underwent WBRT without hippocampal avoidance.
At 4 months, 100 patients treated with the hippocampal-sparing technique who were available for analysis had a 7% decline in the primary endpoint – delayed recall scores from baseline – compared with 30% for historical controls (P = .0003).
Among the 29 patients for whom 6-month data were available, the mean relative decline from baseline in delayed recall was 2% and in immediate recall was 0.7%. In contrast, there was a 3% increase in total recall scores.
The risk of metastasis to the hippocampus was 4.5% during follow-up, Dr. Gondi said.
The Radiation Oncology Therapy Group is currently developing a phase III trial of prophylactic cranial radiation with or without hippocampal avoidance for patients with small cell lung cancer.
The study demonstrates the value of improving and incorporating into practice newer radiation delivery technologies such as IMRT, said Dr. Bruce G. Haffty, a radiation oncologist at the Cancer Institute of New Jersey in New Brunswick, and ASTRO president-elect.
"It’s nice to have that technology available, and it’s now nice to see that we can use that technology to [reduce] memory loss and improve quality of life for our patients undergoing whole brain radiation therapy," he said.
Dr. Haffty moderated the briefing, but was not involved in the study.
RTOG 0993 was supported by the National Cancer Institute. Dr. Gondi and Dr. Haffty reported having no relevant financial conflicts.
AT THE ASTRO ANNUAL MEETING
Major finding: Patients who underwent whole brain radiation therapy with hippocampal avoidance had a 7% decline in delayed recall at 4 months, compared with 30% for historical controls.
Data source: A prospective phase II clinical trial of 113 patients vs. historical controls.
Disclosures: RTOG 0993 was supported by the National Cancer Institute. Dr. Gondi and Dr. Haffty reported having no relevant financial conflicts.
Prolactin measure didn’t help localize pituitary adenoma
SAN FRANCISCO – Measurements of prolactin levels during inferior petrosal sinus sampling did not help localize pituitary adenomas in patients with Cushing’s disease in a study of 28 patients, contradicting findings from a previous study of 28 patients.
The value of prolactin measurements in tumor localization using inferior petrosal sinus sampling (IPSS) remains unclear and needs further study in a larger, prospective study, Dr. Susmeeta T. Sharma said at the Endocrine Society’s Annual Meeting. The current and previous studies were retrospective analyses.
Although IPSS has been considered the standard test in patients with ACTH-dependent Cushing’s syndrome to differentiate between ectopic ACTH secretion and Cushing’s disease, there has been controversy about its value in localizing adenomas within the pituitary gland once a biochemical diagnosis of Cushing’s disease has been made. Various studies that used an intersinus ACTH ratio of 1.4 or greater before or after corticotropin-releasing hormone (CRH) stimulation have reported success rates as low as 50% and as high as 100% for tumor location.
A previous retrospective study of 28 patients with Cushing’s disease reported that adjusting the ACTH intersinus gradient by levels of prolactin before or after CRH stimulation, and combining the prolactin-adjusted ACTH intersinus ratio, improved pituitary adenoma localization. Magnetic resonance imaging (MRI) alone correctly localized the pituitary adenoma in 17 patients (61%), a prolactin-adjusted ACTH intersinus ratio of at least 1.4 improved the localization rate to 21 patients (75%), and combining MRI and the prolactin-adjusted ACTH intersinus ratio improved localization further to 23 patients, or 82% (Clin. Endocrinol. 2012;77:268-74).
The findings inspired the current retrospective study. The investigators looked at prolactin levels measured in stored petrosal and peripheral venous samples at baseline and at the time of peak ACTH levels after CRH stimulation for 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013. The investigators calculated prolactin-adjusted values by dividing each ACTH value by the concomitant ipsilateral prolactin value. They used an intersinus ACTH ratio of 1.4 or greater to predict tumor location.
At surgery, 26 patients had a single lateral tumor (meaning its epicenter was not in the midline), 1 patient had a central microadenoma, and 1 patient had a macroadenoma, reported Dr. Sharma of the National Institute of Child Health and Human Development, Bethesda, Md.
MRI findings accurately identified the location of 21 of the 26 lateral tumors (81%), compared with accurate localization in 18 patients using either the unadjusted ACTH intersinus ratio or the prolactin-adjusted ACTH intersinus ratio (69% for each), she said.
Incorrect tumor localization occurred with one patient using MRI alone and seven patients using either ratio. In four patients whose tumors could not be localized by MRI, the uncorrected and prolactin-adjusted ratios localized one tumor correctly and three tumors incorrectly. Only MRI correctly localized the one central microadenoma.
"We did not find any difference in localization rates by measurement of prolactin during IPSS," she said. The small size of the study and its retrospective design invite further research in a more robust study.
Dr. Sharma reported having no financial disclosures.
On Twitter @sherryboschert
SAN FRANCISCO – Measurements of prolactin levels during inferior petrosal sinus sampling did not help localize pituitary adenomas in patients with Cushing’s disease in a study of 28 patients, contradicting findings from a previous study of 28 patients.
The value of prolactin measurements in tumor localization using inferior petrosal sinus sampling (IPSS) remains unclear and needs further study in a larger, prospective study, Dr. Susmeeta T. Sharma said at the Endocrine Society’s Annual Meeting. The current and previous studies were retrospective analyses.
Although IPSS has been considered the standard test in patients with ACTH-dependent Cushing’s syndrome to differentiate between ectopic ACTH secretion and Cushing’s disease, there has been controversy about its value in localizing adenomas within the pituitary gland once a biochemical diagnosis of Cushing’s disease has been made. Various studies that used an intersinus ACTH ratio of 1.4 or greater before or after corticotropin-releasing hormone (CRH) stimulation have reported success rates as low as 50% and as high as 100% for tumor location.
A previous retrospective study of 28 patients with Cushing’s disease reported that adjusting the ACTH intersinus gradient by levels of prolactin before or after CRH stimulation, and combining the prolactin-adjusted ACTH intersinus ratio, improved pituitary adenoma localization. Magnetic resonance imaging (MRI) alone correctly localized the pituitary adenoma in 17 patients (61%), a prolactin-adjusted ACTH intersinus ratio of at least 1.4 improved the localization rate to 21 patients (75%), and combining MRI and the prolactin-adjusted ACTH intersinus ratio improved localization further to 23 patients, or 82% (Clin. Endocrinol. 2012;77:268-74).
The findings inspired the current retrospective study. The investigators looked at prolactin levels measured in stored petrosal and peripheral venous samples at baseline and at the time of peak ACTH levels after CRH stimulation for 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013. The investigators calculated prolactin-adjusted values by dividing each ACTH value by the concomitant ipsilateral prolactin value. They used an intersinus ACTH ratio of 1.4 or greater to predict tumor location.
At surgery, 26 patients had a single lateral tumor (meaning its epicenter was not in the midline), 1 patient had a central microadenoma, and 1 patient had a macroadenoma, reported Dr. Sharma of the National Institute of Child Health and Human Development, Bethesda, Md.
MRI findings accurately identified the location of 21 of the 26 lateral tumors (81%), compared with accurate localization in 18 patients using either the unadjusted ACTH intersinus ratio or the prolactin-adjusted ACTH intersinus ratio (69% for each), she said.
Incorrect tumor localization occurred with one patient using MRI alone and seven patients using either ratio. In four patients whose tumors could not be localized by MRI, the uncorrected and prolactin-adjusted ratios localized one tumor correctly and three tumors incorrectly. Only MRI correctly localized the one central microadenoma.
"We did not find any difference in localization rates by measurement of prolactin during IPSS," she said. The small size of the study and its retrospective design invite further research in a more robust study.
Dr. Sharma reported having no financial disclosures.
On Twitter @sherryboschert
SAN FRANCISCO – Measurements of prolactin levels during inferior petrosal sinus sampling did not help localize pituitary adenomas in patients with Cushing’s disease in a study of 28 patients, contradicting findings from a previous study of 28 patients.
The value of prolactin measurements in tumor localization using inferior petrosal sinus sampling (IPSS) remains unclear and needs further study in a larger, prospective study, Dr. Susmeeta T. Sharma said at the Endocrine Society’s Annual Meeting. The current and previous studies were retrospective analyses.
Although IPSS has been considered the standard test in patients with ACTH-dependent Cushing’s syndrome to differentiate between ectopic ACTH secretion and Cushing’s disease, there has been controversy about its value in localizing adenomas within the pituitary gland once a biochemical diagnosis of Cushing’s disease has been made. Various studies that used an intersinus ACTH ratio of 1.4 or greater before or after corticotropin-releasing hormone (CRH) stimulation have reported success rates as low as 50% and as high as 100% for tumor location.
A previous retrospective study of 28 patients with Cushing’s disease reported that adjusting the ACTH intersinus gradient by levels of prolactin before or after CRH stimulation, and combining the prolactin-adjusted ACTH intersinus ratio, improved pituitary adenoma localization. Magnetic resonance imaging (MRI) alone correctly localized the pituitary adenoma in 17 patients (61%), a prolactin-adjusted ACTH intersinus ratio of at least 1.4 improved the localization rate to 21 patients (75%), and combining MRI and the prolactin-adjusted ACTH intersinus ratio improved localization further to 23 patients, or 82% (Clin. Endocrinol. 2012;77:268-74).
The findings inspired the current retrospective study. The investigators looked at prolactin levels measured in stored petrosal and peripheral venous samples at baseline and at the time of peak ACTH levels after CRH stimulation for 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013. The investigators calculated prolactin-adjusted values by dividing each ACTH value by the concomitant ipsilateral prolactin value. They used an intersinus ACTH ratio of 1.4 or greater to predict tumor location.
At surgery, 26 patients had a single lateral tumor (meaning its epicenter was not in the midline), 1 patient had a central microadenoma, and 1 patient had a macroadenoma, reported Dr. Sharma of the National Institute of Child Health and Human Development, Bethesda, Md.
MRI findings accurately identified the location of 21 of the 26 lateral tumors (81%), compared with accurate localization in 18 patients using either the unadjusted ACTH intersinus ratio or the prolactin-adjusted ACTH intersinus ratio (69% for each), she said.
Incorrect tumor localization occurred with one patient using MRI alone and seven patients using either ratio. In four patients whose tumors could not be localized by MRI, the uncorrected and prolactin-adjusted ratios localized one tumor correctly and three tumors incorrectly. Only MRI correctly localized the one central microadenoma.
"We did not find any difference in localization rates by measurement of prolactin during IPSS," she said. The small size of the study and its retrospective design invite further research in a more robust study.
Dr. Sharma reported having no financial disclosures.
On Twitter @sherryboschert
AT ENDO 2013
Major finding: The unadjusted and prolactin-adjusted ACTH intersinus ratios correctly localized 18 of 26 lateral pituitary adenomas (69%), compared with 21 localized by MRI (81%).
Data source: Retrospective study of 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013.
Disclosures: Dr. Sharma reported having no financial disclosures.
Good survival rates with temozolomide CRT for high-risk, low-grade gliomas
CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.
At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.
Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.
Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.
The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.
The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).
A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m2 per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m2 per day for days 1-5 of each 28-day cycle for a total of 12 cycles.
The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.
The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.
In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).
In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.
Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.
In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."
In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.
The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.
CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.
At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.
Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.
Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.
The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.
The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).
A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m2 per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m2 per day for days 1-5 of each 28-day cycle for a total of 12 cycles.
The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.
The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.
In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).
In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.
Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.
In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."
In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.
The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.
CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.
At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.
Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.
Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.
The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.
The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).
A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m2 per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m2 per day for days 1-5 of each 28-day cycle for a total of 12 cycles.
The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.
The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.
In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).
In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.
Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.
In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."
In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.
The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.
AT THE ASCO ANNUAL MEETING 2013
Major finding: With temozolomide chemoradiotherapy, 3-year overall survival was 73% for patients with low-grade gliomas and three or more risk factors for worse prognosis, compared with 54% for historical controls (P less than .001).
Data source: Single-arm, prospective phase II study in 129 patients compared with historical controls.
Disclosures: The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.
Donepezil fails to improve cognition after brain irradiation
CHICAGO – Donepezil proved no better than placebo at improving overall cognitive function among 198 patients who had undergone partial or whole brain irradiation for brain tumors, investigators reported at the annual meeting of the American Society of Clinical Oncology.
A randomized, double-blind, multicenter phase III trial found no significant differences between donepezil (Aricept) and placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory, said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest Baptist Medical Center in Winston-Salem, N.C.
Among patients with more cognitive problems at baseline, however, there was a significant benefit in verbal memory for patients on donepezil, compared with controls (P = .005), and a trend toward preservation of motor speed and dexterity, Dr. Rapp said.
"We have to continue looking for effective treatments for cognitive symptoms in this population. It has a big impact on patients," he said.
Previous studies indicated that more than half of patients who receive partial or whole brain irradiation for tumors will have cognitive deficits, and that about 12% will develop some form of dementia. Cognitive problems have a major impact on patient quality of life, and anything clinicians can do to preserve or improve patient mental faculties is important, Dr. Rapp said.
The study was designed to test whether donepezil, an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate cognitive decline from Alzheimer’s disease, could have a similar neuroprotective effect following whole brain irradiation.
Investigators enrolled 198 patients 6 months after they received at least 30 Gy of brain irradiation. Following a baseline evaluation, patients were randomized to receive either 5-10 mg daily of oral donepezil or placebo for 24 weeks, with an interim assessment performed at 12 weeks.
The study looked at the effect of the drug on cognitive functioning and on measures of fatigue, mood, and quality of life.
The patients were assessed at baseline for cognitive function, and at 12 and 24 weeks with the Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure-modified (a measure of visual spatial ability, memory, and planning ability), Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard (a measure of dexterity and motor control).
Both study arms showed significant improvement in cognitive composite scores over baseline (P less than .01 for both), but the degree of improvement did not differ significantly between arms. Similarly, there were no significant differences between the treatment arms in any of the test domains, Dr. Rapp said.
Among patients with greater baseline cognitive deficits, as measured by a score of less than 51 on the FACT Brain subscale, there was also significant improvement over baseline but no between-group difference, he reported.
Donepezil was significantly better than placebo control in this subgroup for improvement in performance on the recognition portion of the Hopkins Verbal Learning Test, which measures verbal memory, and donepezil danced on the edge of significance at preserving motor speed and dexterity as measured by the Grooved Pegboard-Dominant Hand test but never crossed the line (P = .06), he said.
Adverse events were similar between the groups, and the patients assigned to donepezil appeared to tolerate it well, Dr. Rapp said.
Dr. Robin Grant of the Center for Clinical Brain Sciences at the University of Edinburgh, the invited discussant, said that the study was very well designed. He noted, however, "that there was no specified level of cognitive deficit at the time of [study] entry, and I think if you look at moderate to severely affected patients then you’re more likely to be able to show a change there," he said.
He added that it would be interesting to see results from the Grooved Pegboard test performed with the contralateral rather than dominant hand.
The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.
CHICAGO – Donepezil proved no better than placebo at improving overall cognitive function among 198 patients who had undergone partial or whole brain irradiation for brain tumors, investigators reported at the annual meeting of the American Society of Clinical Oncology.
A randomized, double-blind, multicenter phase III trial found no significant differences between donepezil (Aricept) and placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory, said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest Baptist Medical Center in Winston-Salem, N.C.
Among patients with more cognitive problems at baseline, however, there was a significant benefit in verbal memory for patients on donepezil, compared with controls (P = .005), and a trend toward preservation of motor speed and dexterity, Dr. Rapp said.
"We have to continue looking for effective treatments for cognitive symptoms in this population. It has a big impact on patients," he said.
Previous studies indicated that more than half of patients who receive partial or whole brain irradiation for tumors will have cognitive deficits, and that about 12% will develop some form of dementia. Cognitive problems have a major impact on patient quality of life, and anything clinicians can do to preserve or improve patient mental faculties is important, Dr. Rapp said.
The study was designed to test whether donepezil, an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate cognitive decline from Alzheimer’s disease, could have a similar neuroprotective effect following whole brain irradiation.
Investigators enrolled 198 patients 6 months after they received at least 30 Gy of brain irradiation. Following a baseline evaluation, patients were randomized to receive either 5-10 mg daily of oral donepezil or placebo for 24 weeks, with an interim assessment performed at 12 weeks.
The study looked at the effect of the drug on cognitive functioning and on measures of fatigue, mood, and quality of life.
The patients were assessed at baseline for cognitive function, and at 12 and 24 weeks with the Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure-modified (a measure of visual spatial ability, memory, and planning ability), Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard (a measure of dexterity and motor control).
Both study arms showed significant improvement in cognitive composite scores over baseline (P less than .01 for both), but the degree of improvement did not differ significantly between arms. Similarly, there were no significant differences between the treatment arms in any of the test domains, Dr. Rapp said.
Among patients with greater baseline cognitive deficits, as measured by a score of less than 51 on the FACT Brain subscale, there was also significant improvement over baseline but no between-group difference, he reported.
Donepezil was significantly better than placebo control in this subgroup for improvement in performance on the recognition portion of the Hopkins Verbal Learning Test, which measures verbal memory, and donepezil danced on the edge of significance at preserving motor speed and dexterity as measured by the Grooved Pegboard-Dominant Hand test but never crossed the line (P = .06), he said.
Adverse events were similar between the groups, and the patients assigned to donepezil appeared to tolerate it well, Dr. Rapp said.
Dr. Robin Grant of the Center for Clinical Brain Sciences at the University of Edinburgh, the invited discussant, said that the study was very well designed. He noted, however, "that there was no specified level of cognitive deficit at the time of [study] entry, and I think if you look at moderate to severely affected patients then you’re more likely to be able to show a change there," he said.
He added that it would be interesting to see results from the Grooved Pegboard test performed with the contralateral rather than dominant hand.
The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.
CHICAGO – Donepezil proved no better than placebo at improving overall cognitive function among 198 patients who had undergone partial or whole brain irradiation for brain tumors, investigators reported at the annual meeting of the American Society of Clinical Oncology.
A randomized, double-blind, multicenter phase III trial found no significant differences between donepezil (Aricept) and placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory, said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest Baptist Medical Center in Winston-Salem, N.C.
Among patients with more cognitive problems at baseline, however, there was a significant benefit in verbal memory for patients on donepezil, compared with controls (P = .005), and a trend toward preservation of motor speed and dexterity, Dr. Rapp said.
"We have to continue looking for effective treatments for cognitive symptoms in this population. It has a big impact on patients," he said.
Previous studies indicated that more than half of patients who receive partial or whole brain irradiation for tumors will have cognitive deficits, and that about 12% will develop some form of dementia. Cognitive problems have a major impact on patient quality of life, and anything clinicians can do to preserve or improve patient mental faculties is important, Dr. Rapp said.
The study was designed to test whether donepezil, an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate cognitive decline from Alzheimer’s disease, could have a similar neuroprotective effect following whole brain irradiation.
Investigators enrolled 198 patients 6 months after they received at least 30 Gy of brain irradiation. Following a baseline evaluation, patients were randomized to receive either 5-10 mg daily of oral donepezil or placebo for 24 weeks, with an interim assessment performed at 12 weeks.
The study looked at the effect of the drug on cognitive functioning and on measures of fatigue, mood, and quality of life.
The patients were assessed at baseline for cognitive function, and at 12 and 24 weeks with the Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure-modified (a measure of visual spatial ability, memory, and planning ability), Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard (a measure of dexterity and motor control).
Both study arms showed significant improvement in cognitive composite scores over baseline (P less than .01 for both), but the degree of improvement did not differ significantly between arms. Similarly, there were no significant differences between the treatment arms in any of the test domains, Dr. Rapp said.
Among patients with greater baseline cognitive deficits, as measured by a score of less than 51 on the FACT Brain subscale, there was also significant improvement over baseline but no between-group difference, he reported.
Donepezil was significantly better than placebo control in this subgroup for improvement in performance on the recognition portion of the Hopkins Verbal Learning Test, which measures verbal memory, and donepezil danced on the edge of significance at preserving motor speed and dexterity as measured by the Grooved Pegboard-Dominant Hand test but never crossed the line (P = .06), he said.
Adverse events were similar between the groups, and the patients assigned to donepezil appeared to tolerate it well, Dr. Rapp said.
Dr. Robin Grant of the Center for Clinical Brain Sciences at the University of Edinburgh, the invited discussant, said that the study was very well designed. He noted, however, "that there was no specified level of cognitive deficit at the time of [study] entry, and I think if you look at moderate to severely affected patients then you’re more likely to be able to show a change there," he said.
He added that it would be interesting to see results from the Grooved Pegboard test performed with the contralateral rather than dominant hand.
The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.
AT THE ASCO ANNUAL MEETING 2013
Major finding: There were no significant differences between donepezil or placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory.
Data source: Randomized, double-blind, placebo-controlled trial of 198 patients after partial or whole brain irradiation.
Disclosures: The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.
Frontline bevacizumab fails to boost glioblastoma survival in key trials
CHICAGO – Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.
Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.
Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.
Median progression-free survival reached 10.7 months in the bevacizumab arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the bevacizumab arm had significantly worse neurocognitive and overall symptom scores over time.
"We feel that bevacizumab remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment," he said at a press briefing prior to his presentation.
Outcomes contrast with Avaglio study
Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the ASCO annual meeting.
The Avaglio investigators found that adding bevacizumab to radiotherapy and temozolomide "achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma," Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.
The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on bevacizumab, but did not look at neurocognitive outcomes.
Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 6.2 months in 463 patients in its radiation, temozolomide, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).
However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.
Bevacizumab misses RTOG targets
The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with temozolomide for 3 weeks followed by chemoradiation with temozolomide and either bevacizumab or placebo for 6-12 maintenance cycles.
The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on, bevacizumab. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.
In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).
(The results of the GLARIUS trial, also reported at this meeting, showed that bevacizumab combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than temozolomide chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the bevacizumab-irinotecan combination.)
As noted, in RTOG 0825, patients in the bevacizumab arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).
In contrast, patients on bevacizumab in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.
Why the differences?
Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.
Another possibility to account for the worsening neurocognitive function with bevacizumab is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.
Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as bevacizumab, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.
But although bevacizumab has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.
Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of bevacizumab to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.
"Despite these new data demonstrating its limitation, I feel very strongly that bevacizumab represents the single most important agent in glioblastoma since temozolomide, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options," Dr. Fine concluded.
The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.
CHICAGO – Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.
Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.
Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.
Median progression-free survival reached 10.7 months in the bevacizumab arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the bevacizumab arm had significantly worse neurocognitive and overall symptom scores over time.
"We feel that bevacizumab remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment," he said at a press briefing prior to his presentation.
Outcomes contrast with Avaglio study
Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the ASCO annual meeting.
The Avaglio investigators found that adding bevacizumab to radiotherapy and temozolomide "achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma," Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.
The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on bevacizumab, but did not look at neurocognitive outcomes.
Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 6.2 months in 463 patients in its radiation, temozolomide, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).
However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.
Bevacizumab misses RTOG targets
The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with temozolomide for 3 weeks followed by chemoradiation with temozolomide and either bevacizumab or placebo for 6-12 maintenance cycles.
The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on, bevacizumab. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.
In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).
(The results of the GLARIUS trial, also reported at this meeting, showed that bevacizumab combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than temozolomide chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the bevacizumab-irinotecan combination.)
As noted, in RTOG 0825, patients in the bevacizumab arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).
In contrast, patients on bevacizumab in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.
Why the differences?
Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.
Another possibility to account for the worsening neurocognitive function with bevacizumab is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.
Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as bevacizumab, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.
But although bevacizumab has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.
Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of bevacizumab to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.
"Despite these new data demonstrating its limitation, I feel very strongly that bevacizumab represents the single most important agent in glioblastoma since temozolomide, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options," Dr. Fine concluded.
The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.
CHICAGO – Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.
Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.
Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.
Median progression-free survival reached 10.7 months in the bevacizumab arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the bevacizumab arm had significantly worse neurocognitive and overall symptom scores over time.
"We feel that bevacizumab remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment," he said at a press briefing prior to his presentation.
Outcomes contrast with Avaglio study
Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the ASCO annual meeting.
The Avaglio investigators found that adding bevacizumab to radiotherapy and temozolomide "achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma," Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.
The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on bevacizumab, but did not look at neurocognitive outcomes.
Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 6.2 months in 463 patients in its radiation, temozolomide, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).
However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.
Bevacizumab misses RTOG targets
The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with temozolomide for 3 weeks followed by chemoradiation with temozolomide and either bevacizumab or placebo for 6-12 maintenance cycles.
The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on, bevacizumab. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.
In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).
(The results of the GLARIUS trial, also reported at this meeting, showed that bevacizumab combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than temozolomide chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the bevacizumab-irinotecan combination.)
As noted, in RTOG 0825, patients in the bevacizumab arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).
In contrast, patients on bevacizumab in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.
Why the differences?
Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.
Another possibility to account for the worsening neurocognitive function with bevacizumab is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.
Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as bevacizumab, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.
But although bevacizumab has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.
Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of bevacizumab to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.
"Despite these new data demonstrating its limitation, I feel very strongly that bevacizumab represents the single most important agent in glioblastoma since temozolomide, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options," Dr. Fine concluded.
The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.
AT THE ASCO ANNUAL MEETING 2013
Major finding: Median overall survival for those assigned to radiation, temozolomide, and placebo was 16.1 months, vs. 15.7 months for patients assigned to radiation, temozolomide, and bevacizumab in one study.
Data source: A randomized, double-blind placebo controlled trial in 637 patients with newly diagnosed glioblastoma.
Disclosures: The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed that he was a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.
Bevacizumab plus irinotecan beats temozolomide in stalling glioblastoma
CHICAGO – The combination of bevacizumab and irinotecan far outshone tenozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.
In the phase II GLARIUS trial, 79.6% of patients treated with bevacizumab (Avastin) and irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.
Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.
A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).
"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.
The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O6-methylguanine-DNA methyltransferase)-unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.
Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.
All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).
The experimental arm received bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance bevacizumab at the same dose and irinotecan 125 mg/m2 every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m2. The standard therapy arm was given temozolomide 75 mg/m2 daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m2 for 5 days every 4 weeks.
In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).
In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.
The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.
"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.
Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.
The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.
CHICAGO – The combination of bevacizumab and irinotecan far outshone tenozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.
In the phase II GLARIUS trial, 79.6% of patients treated with bevacizumab (Avastin) and irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.
Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.
A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).
"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.
The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O6-methylguanine-DNA methyltransferase)-unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.
Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.
All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).
The experimental arm received bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance bevacizumab at the same dose and irinotecan 125 mg/m2 every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m2. The standard therapy arm was given temozolomide 75 mg/m2 daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m2 for 5 days every 4 weeks.
In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).
In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.
The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.
"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.
Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.
The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.
CHICAGO – The combination of bevacizumab and irinotecan far outshone tenozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.
In the phase II GLARIUS trial, 79.6% of patients treated with bevacizumab (Avastin) and irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.
Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.
A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).
"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.
The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O6-methylguanine-DNA methyltransferase)-unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.
Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.
All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).
The experimental arm received bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance bevacizumab at the same dose and irinotecan 125 mg/m2 every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m2. The standard therapy arm was given temozolomide 75 mg/m2 daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m2 for 5 days every 4 weeks.
In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).
In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.
The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.
"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.
Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.
The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.
AT ASCO ANNUAL MEETING 2013
Major finding: The 6-month progression-free survival 6 months after randomization was 79.6% for patients treated with bevacizumab and irinotecan vs. 41.3% with temozolomide.
Data source: Randomized controlled trial in 170 patients with MGMT-unmethylated glioblastoma from 22 centers in Germany.
Disclosures: The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.
