Neuro-oncology

The Food and Drug Administration is investigating the risk of brain deposits after recurring use of gadolinium-based contrast agents for MRI, the agency announced in a statement.

Studies suggest that gadolinium-based contrast agent (GBCA) deposits may stay in the brains of patients who have four or more contrast MRI scans, though it is unknown whether these deposits cause adverse effects, the FDA said.

GBCAs are usually expelled through the kidneys, but may remain in the brain after repeated exposure. FDA’s National Center for Toxicological

Research will further investigate safety risks in consultation with researchers and industry, the statement said.

The FDA is not requiring manufacturers to change the labels of GBCA products until more information is known. The agency is, however, recommending that clinicians limit GBCA use to situations in which it would be necessary for patient care.

“Health care professionals are also urged to reassess the necessity of repetitive GBCA MRIs in established treatment protocols,” the FDA said.

Patients may report side effects and adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

[email protected]

The Food and Drug Administration is investigating the risk of brain deposits after recurring use of gadolinium-based contrast agents for MRI, the agency announced in a statement.

Studies suggest that gadolinium-based contrast agent (GBCA) deposits may stay in the brains of patients who have four or more contrast MRI scans, though it is unknown whether these deposits cause adverse effects, the FDA said.

GBCAs are usually expelled through the kidneys, but may remain in the brain after repeated exposure. FDA’s National Center for Toxicological

Research will further investigate safety risks in consultation with researchers and industry, the statement said.

The FDA is not requiring manufacturers to change the labels of GBCA products until more information is known. The agency is, however, recommending that clinicians limit GBCA use to situations in which it would be necessary for patient care.

“Health care professionals are also urged to reassess the necessity of repetitive GBCA MRIs in established treatment protocols,” the FDA said.

Patients may report side effects and adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

[email protected]

The Food and Drug Administration is investigating the risk of brain deposits after recurring use of gadolinium-based contrast agents for MRI, the agency announced in a statement.

Studies suggest that gadolinium-based contrast agent (GBCA) deposits may stay in the brains of patients who have four or more contrast MRI scans, though it is unknown whether these deposits cause adverse effects, the FDA said.

GBCAs are usually expelled through the kidneys, but may remain in the brain after repeated exposure. FDA’s National Center for Toxicological

Research will further investigate safety risks in consultation with researchers and industry, the statement said.

The FDA is not requiring manufacturers to change the labels of GBCA products until more information is known. The agency is, however, recommending that clinicians limit GBCA use to situations in which it would be necessary for patient care.

“Health care professionals are also urged to reassess the necessity of repetitive GBCA MRIs in established treatment protocols,” the FDA said.

Patients may report side effects and adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

[email protected]

CHICAGO – It’s getting very personal in oncology, and that’s a very good thing.

At the annual meeting of the American Society of Clinical Oncology, major cancer organizations announced new precision medicine initiatives that will attempt to match patients who have advanced cancers with the best available therapies based not on the location or histologic subtypes of their tumors, but on specific molecular abnormalities.

The National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial will begin enrolling patients in July 2015. The study’s objective is “to understand the relative efficacy of the same therapy applied to oncogene-defined subsets across the entire cancer population as defined by site of origin or tumor histology,” said co–principal investigator Dr. Keith T. Flaherty of Harvard Medical School, Boston.

“This is the beginning, not the end, in terms of how we think about applying these therapies,” he said at a briefing that was held to announce the start of trial enrollment and a second initiative – the Targeted Agent and Profiling Utilization Registry (TAPUR) Study – by ASCO in cooperation with major pharmaceutical companies.

NCI-MATCH

NCI-MATCH is a phase II trial that will be operated through the National Clinical Trials Network. Oncologists at participating centers throughout the United States can enroll patients aged 18 years and older who have solid tumors or lymphomas that have relapsed or are refractory to conventional therapy, or who have a type of cancer for which no effective, consensus-based therapy is available.

Investigators plan to screen 3,000 patients initially, with the goal of enrolling 1,000 patients distributed among several substudies that will be evaluating specific drugs against specific molecular targets.

Patients will undergo biopsy at study entry, and their tumors will be subjected to genomic analysis to detect specific, targetable molecular abnormalities.

If a patient has a specific abnormality that is being explored in a current substudy, that patient will be further evaluated to determine whether he or she meets the eligibility criteria for that trial arm. Once enrolled, patients can remain on therapy until disease progression. The therapies will include both currently marketed agents and investigational therapies contributed by drug companies. Most of the trial arms will explore monotherapy with a targeted agent, but a few may investigate combinations which have accumulated enough safety and efficacy data to suggest that they might work against a specific molecular target.

The primary endpoint will be overall response rate, with a secondary endpoint of 6-month progression-free survival (PFS).

“This holds promise to bring faster cures to millions of Americans who so desperately need them,” ASCO past president Dr. Clifford A. Hudis said at the briefing.

TAPUR Trial

In cooperation with major pharmaceutical manufacturers (currently five, with more expected to sign on), ASCO has initiated a study designed to help answer the question, “I’ve got the tumor genome – now what do I do with it?”

The goal of the TAPUR trial, says ASCO Chief Medical Officer Dr. Richard Schilsky, is “to learn from the real world practice of prescribing targeted therapies to patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target.”

The primary objectives are to describe the antitumor activity and toxicity profiles of targeted therapies, and to help patients get access to Food and Drug Administration–approved agents from which they may be able to benefit.

The trial will enroll patients with advanced solid tumors, B-cell non-Hodgkin’s lymphomas, and multiple myelomas for which there are no standard therapies. The patients must have adequate organ function and good performance status (0-2).

Patients will be matched by their personal physicians to specific therapies, if such a match exists; otherwise, they will be treated at the physician’s discretion.

The primary endpoint of the study will be overall response rates by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints will be PFS, OS, time on treatment, grade 3 or greater adverse events, and serious adverse event. The investigators plan to begin patient enrollment in the fourth quarter of 2015.

Current industry partners include AstraZeneca, Bristol Myers Squibb, Eli Lilly, Genentech, and Pfizer.

The NCI-MATCH study is funded by the National Institutes of Health. Dr. Flaherty has received NIH research grants. Dr. Hudis disclosed ties to AstraZeneca, Sanofi-Aventis, Amgen, Bristol-Myers Squibb, Genentech, Eli Lilly, Novartis, Ortho Biotech, Pfizer, and Roche. Dr. Schilsky disclosed no relevant conflicts of interest.

CHICAGO – It’s getting very personal in oncology, and that’s a very good thing.

At the annual meeting of the American Society of Clinical Oncology, major cancer organizations announced new precision medicine initiatives that will attempt to match patients who have advanced cancers with the best available therapies based not on the location or histologic subtypes of their tumors, but on specific molecular abnormalities.

The National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial will begin enrolling patients in July 2015. The study’s objective is “to understand the relative efficacy of the same therapy applied to oncogene-defined subsets across the entire cancer population as defined by site of origin or tumor histology,” said co–principal investigator Dr. Keith T. Flaherty of Harvard Medical School, Boston.

“This is the beginning, not the end, in terms of how we think about applying these therapies,” he said at a briefing that was held to announce the start of trial enrollment and a second initiative – the Targeted Agent and Profiling Utilization Registry (TAPUR) Study – by ASCO in cooperation with major pharmaceutical companies.

NCI-MATCH

NCI-MATCH is a phase II trial that will be operated through the National Clinical Trials Network. Oncologists at participating centers throughout the United States can enroll patients aged 18 years and older who have solid tumors or lymphomas that have relapsed or are refractory to conventional therapy, or who have a type of cancer for which no effective, consensus-based therapy is available.

Investigators plan to screen 3,000 patients initially, with the goal of enrolling 1,000 patients distributed among several substudies that will be evaluating specific drugs against specific molecular targets.

Patients will undergo biopsy at study entry, and their tumors will be subjected to genomic analysis to detect specific, targetable molecular abnormalities.

If a patient has a specific abnormality that is being explored in a current substudy, that patient will be further evaluated to determine whether he or she meets the eligibility criteria for that trial arm. Once enrolled, patients can remain on therapy until disease progression. The therapies will include both currently marketed agents and investigational therapies contributed by drug companies. Most of the trial arms will explore monotherapy with a targeted agent, but a few may investigate combinations which have accumulated enough safety and efficacy data to suggest that they might work against a specific molecular target.

The primary endpoint will be overall response rate, with a secondary endpoint of 6-month progression-free survival (PFS).

“This holds promise to bring faster cures to millions of Americans who so desperately need them,” ASCO past president Dr. Clifford A. Hudis said at the briefing.

TAPUR Trial

In cooperation with major pharmaceutical manufacturers (currently five, with more expected to sign on), ASCO has initiated a study designed to help answer the question, “I’ve got the tumor genome – now what do I do with it?”

The goal of the TAPUR trial, says ASCO Chief Medical Officer Dr. Richard Schilsky, is “to learn from the real world practice of prescribing targeted therapies to patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target.”

The primary objectives are to describe the antitumor activity and toxicity profiles of targeted therapies, and to help patients get access to Food and Drug Administration–approved agents from which they may be able to benefit.

The trial will enroll patients with advanced solid tumors, B-cell non-Hodgkin’s lymphomas, and multiple myelomas for which there are no standard therapies. The patients must have adequate organ function and good performance status (0-2).

Patients will be matched by their personal physicians to specific therapies, if such a match exists; otherwise, they will be treated at the physician’s discretion.

The primary endpoint of the study will be overall response rates by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints will be PFS, OS, time on treatment, grade 3 or greater adverse events, and serious adverse event. The investigators plan to begin patient enrollment in the fourth quarter of 2015.

Current industry partners include AstraZeneca, Bristol Myers Squibb, Eli Lilly, Genentech, and Pfizer.

The NCI-MATCH study is funded by the National Institutes of Health. Dr. Flaherty has received NIH research grants. Dr. Hudis disclosed ties to AstraZeneca, Sanofi-Aventis, Amgen, Bristol-Myers Squibb, Genentech, Eli Lilly, Novartis, Ortho Biotech, Pfizer, and Roche. Dr. Schilsky disclosed no relevant conflicts of interest.

CHICAGO – It’s getting very personal in oncology, and that’s a very good thing.

At the annual meeting of the American Society of Clinical Oncology, major cancer organizations announced new precision medicine initiatives that will attempt to match patients who have advanced cancers with the best available therapies based not on the location or histologic subtypes of their tumors, but on specific molecular abnormalities.

The National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial will begin enrolling patients in July 2015. The study’s objective is “to understand the relative efficacy of the same therapy applied to oncogene-defined subsets across the entire cancer population as defined by site of origin or tumor histology,” said co–principal investigator Dr. Keith T. Flaherty of Harvard Medical School, Boston.

“This is the beginning, not the end, in terms of how we think about applying these therapies,” he said at a briefing that was held to announce the start of trial enrollment and a second initiative – the Targeted Agent and Profiling Utilization Registry (TAPUR) Study – by ASCO in cooperation with major pharmaceutical companies.

NCI-MATCH

NCI-MATCH is a phase II trial that will be operated through the National Clinical Trials Network. Oncologists at participating centers throughout the United States can enroll patients aged 18 years and older who have solid tumors or lymphomas that have relapsed or are refractory to conventional therapy, or who have a type of cancer for which no effective, consensus-based therapy is available.

Investigators plan to screen 3,000 patients initially, with the goal of enrolling 1,000 patients distributed among several substudies that will be evaluating specific drugs against specific molecular targets.

Patients will undergo biopsy at study entry, and their tumors will be subjected to genomic analysis to detect specific, targetable molecular abnormalities.

If a patient has a specific abnormality that is being explored in a current substudy, that patient will be further evaluated to determine whether he or she meets the eligibility criteria for that trial arm. Once enrolled, patients can remain on therapy until disease progression. The therapies will include both currently marketed agents and investigational therapies contributed by drug companies. Most of the trial arms will explore monotherapy with a targeted agent, but a few may investigate combinations which have accumulated enough safety and efficacy data to suggest that they might work against a specific molecular target.

The primary endpoint will be overall response rate, with a secondary endpoint of 6-month progression-free survival (PFS).

“This holds promise to bring faster cures to millions of Americans who so desperately need them,” ASCO past president Dr. Clifford A. Hudis said at the briefing.

TAPUR Trial

In cooperation with major pharmaceutical manufacturers (currently five, with more expected to sign on), ASCO has initiated a study designed to help answer the question, “I’ve got the tumor genome – now what do I do with it?”

The goal of the TAPUR trial, says ASCO Chief Medical Officer Dr. Richard Schilsky, is “to learn from the real world practice of prescribing targeted therapies to patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target.”

The primary objectives are to describe the antitumor activity and toxicity profiles of targeted therapies, and to help patients get access to Food and Drug Administration–approved agents from which they may be able to benefit.

The trial will enroll patients with advanced solid tumors, B-cell non-Hodgkin’s lymphomas, and multiple myelomas for which there are no standard therapies. The patients must have adequate organ function and good performance status (0-2).

Patients will be matched by their personal physicians to specific therapies, if such a match exists; otherwise, they will be treated at the physician’s discretion.

The primary endpoint of the study will be overall response rates by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints will be PFS, OS, time on treatment, grade 3 or greater adverse events, and serious adverse event. The investigators plan to begin patient enrollment in the fourth quarter of 2015.

Current industry partners include AstraZeneca, Bristol Myers Squibb, Eli Lilly, Genentech, and Pfizer.

The NCI-MATCH study is funded by the National Institutes of Health. Dr. Flaherty has received NIH research grants. Dr. Hudis disclosed ties to AstraZeneca, Sanofi-Aventis, Amgen, Bristol-Myers Squibb, Genentech, Eli Lilly, Novartis, Ortho Biotech, Pfizer, and Roche. Dr. Schilsky disclosed no relevant conflicts of interest.

CHICAGO – Patients with limited brain metastases treated with radiosurgery have a higher risk of cognitive decline if they then undergo whole-brain radiation therapy, researchers reported at the annual meeting of the American Society of Clinical Oncology.

The phase III North Central Cancer Treatment Group (NCCTG)/Alliance trial also found that although whole-brain radiation therapy (WBRT) roughly halved the likelihood of progression in the brain, it did not prolong survival. And quality of life was worse with its use as well.

“We recommend initial treatment with stereotactic radiation alone and close monitoring in order to better preserve cognitive function, and then reserving whole-brain radiation until the time of symptomatic progression,” senior study author Dr. Jan C. Buckner, professor of oncology at the Mayo Clinic, Rochester, Minnesota, said in a press briefing.

He ticked off a list of alternative approaches for avoiding cognitive problems in general for patients with brain tumors: “If at all possible, use either no radiation, low-dose radiation, hippocampal-sparing radiation, or a combination of radiation and memantine as a way to reduce the risk of cognitive decline because essentially, the brain does not like to be radiated.”

ASCO expert Dr. Brian Michael Alexander said, “This scenario is a pretty complex one, and one that I take a lot of time talking to my patients about.” The disconnect between local control and survival with whole-brain radiation may be due to the availability of very good salvage therapies when brain metastases recur (so that recurrence is irrelevant) or a situation wherein progressive disease outside the brain is driving mortality, he proposed.

“If [the latter] is more of the answer, then … the population of patients who are unlikely to have deaths from progression of disease outside the brain may be the only place where you find a benefit for whole-brain radiation therapy,” according to Dr. Alexander, who is also Disease Center Leader of Radiation Oncology and a physician with the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, and an assistant professor of Radiation Oncology at Harvard Medical School, both in Boston.

Given the totality of data today on the risks and benefits of this therapy, “I think the burden of proof is now switched, to say, can we prove that whole-brain radiation therapy is beneficial in a subset of patients?” he maintained, adding that the calculus may be changing with better systemic therapies, such as targeted agents for lung cancer, that may reduce brain metastases.

In their National Institutes of Health–funded trial, Dr. Buckner and colleagues studied 213 adults who had one to three cerebral metastases measuring up to 3 cm in diameter. They were randomly assigned to receive radiosurgery alone or radiosurgery followed by WBRT. Cognitive progression, the trial’s primary endpoint, was assessed with a battery of tests.

With a median follow-up of 7.2 months, the 3-month rate of cognitive progression, defined as a decline of greater than one standard deviation from baseline in any of the six tests used, was 92% in the WBRT group and 64% in the control group (P = .0007). Specifically, the former were more likely to experience declines in immediate recall (30% vs. 8%), delayed recall (51% vs. 20%), and verbal fluency (19% vs. 2%).

The overall difference in cognitive decline persisted at 6 months and there was additionally a trend at 12 months among the small subset of patients still alive. The WBRT group also had significantly worse scores for patient-reported quality of life.

The 3-month rate of failure in the central nervous system was lower for the patients given WBRT (6% vs. 25%, P less than .0001), but overall survival did not differ significantly between groups, either in the entire population or in subgroups. “In spite of imaging evidence of disease control, there was no overall impact on survival in these patients as they died of other causes,” reported Dr. Buckner.

In the session where the results were presented, invited discussant Dr. Andrew B. Lassman, the John Harris Associate Professor of Neurology and the Chief of Neuro-oncology at Columbia University Medical Center, New York, said, “I think there are other interpretations [of the findings] when placing this study in the context of other trials for brain metastases.”

“First, whole-brain radiotherapy does increase survival in the appropriate context. Second, deferring whole-brain radiotherapy leads to more rapid and more numerous recurrences of brain metastases, which also cause neurocognitive injury,” he elaborated. “Accordingly, whole-brain radiotherapy should be used in selected cases when brain metastases are a life-limiting site of disease. This is a form of precision medicine.”

Adequate assessment of any survival benefit of this therapy requires appropriate patient selection, Dr. Lassman maintained. Therefore, ongoing analysis of the trial’s results according to patients’ graded prognostic assessment (GPA) scores are eagerly awaited.

“Whole-brain radiotherapy remains a useful tool in the appropriate context that should not be discarded, but it is a crude tool with significant toxicities that is now over 60 years old. Refinements and new approaches are needed and in development,” he concluded.

Dr. Buckner disclosed that he has a consulting or advisory role with Merck Serono and is provided with travel, accommodations, and expenses by Genentech/Roche. The trial was funded by the National Institutes of Health.

CHICAGO – Patients with limited brain metastases treated with radiosurgery have a higher risk of cognitive decline if they then undergo whole-brain radiation therapy, researchers reported at the annual meeting of the American Society of Clinical Oncology.

The phase III North Central Cancer Treatment Group (NCCTG)/Alliance trial also found that although whole-brain radiation therapy (WBRT) roughly halved the likelihood of progression in the brain, it did not prolong survival. And quality of life was worse with its use as well.

“We recommend initial treatment with stereotactic radiation alone and close monitoring in order to better preserve cognitive function, and then reserving whole-brain radiation until the time of symptomatic progression,” senior study author Dr. Jan C. Buckner, professor of oncology at the Mayo Clinic, Rochester, Minnesota, said in a press briefing.

He ticked off a list of alternative approaches for avoiding cognitive problems in general for patients with brain tumors: “If at all possible, use either no radiation, low-dose radiation, hippocampal-sparing radiation, or a combination of radiation and memantine as a way to reduce the risk of cognitive decline because essentially, the brain does not like to be radiated.”

ASCO expert Dr. Brian Michael Alexander said, “This scenario is a pretty complex one, and one that I take a lot of time talking to my patients about.” The disconnect between local control and survival with whole-brain radiation may be due to the availability of very good salvage therapies when brain metastases recur (so that recurrence is irrelevant) or a situation wherein progressive disease outside the brain is driving mortality, he proposed.

“If [the latter] is more of the answer, then … the population of patients who are unlikely to have deaths from progression of disease outside the brain may be the only place where you find a benefit for whole-brain radiation therapy,” according to Dr. Alexander, who is also Disease Center Leader of Radiation Oncology and a physician with the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, and an assistant professor of Radiation Oncology at Harvard Medical School, both in Boston.

Given the totality of data today on the risks and benefits of this therapy, “I think the burden of proof is now switched, to say, can we prove that whole-brain radiation therapy is beneficial in a subset of patients?” he maintained, adding that the calculus may be changing with better systemic therapies, such as targeted agents for lung cancer, that may reduce brain metastases.

In their National Institutes of Health–funded trial, Dr. Buckner and colleagues studied 213 adults who had one to three cerebral metastases measuring up to 3 cm in diameter. They were randomly assigned to receive radiosurgery alone or radiosurgery followed by WBRT. Cognitive progression, the trial’s primary endpoint, was assessed with a battery of tests.

With a median follow-up of 7.2 months, the 3-month rate of cognitive progression, defined as a decline of greater than one standard deviation from baseline in any of the six tests used, was 92% in the WBRT group and 64% in the control group (P = .0007). Specifically, the former were more likely to experience declines in immediate recall (30% vs. 8%), delayed recall (51% vs. 20%), and verbal fluency (19% vs. 2%).

The overall difference in cognitive decline persisted at 6 months and there was additionally a trend at 12 months among the small subset of patients still alive. The WBRT group also had significantly worse scores for patient-reported quality of life.

The 3-month rate of failure in the central nervous system was lower for the patients given WBRT (6% vs. 25%, P less than .0001), but overall survival did not differ significantly between groups, either in the entire population or in subgroups. “In spite of imaging evidence of disease control, there was no overall impact on survival in these patients as they died of other causes,” reported Dr. Buckner.

In the session where the results were presented, invited discussant Dr. Andrew B. Lassman, the John Harris Associate Professor of Neurology and the Chief of Neuro-oncology at Columbia University Medical Center, New York, said, “I think there are other interpretations [of the findings] when placing this study in the context of other trials for brain metastases.”

“First, whole-brain radiotherapy does increase survival in the appropriate context. Second, deferring whole-brain radiotherapy leads to more rapid and more numerous recurrences of brain metastases, which also cause neurocognitive injury,” he elaborated. “Accordingly, whole-brain radiotherapy should be used in selected cases when brain metastases are a life-limiting site of disease. This is a form of precision medicine.”

Adequate assessment of any survival benefit of this therapy requires appropriate patient selection, Dr. Lassman maintained. Therefore, ongoing analysis of the trial’s results according to patients’ graded prognostic assessment (GPA) scores are eagerly awaited.

“Whole-brain radiotherapy remains a useful tool in the appropriate context that should not be discarded, but it is a crude tool with significant toxicities that is now over 60 years old. Refinements and new approaches are needed and in development,” he concluded.

Dr. Buckner disclosed that he has a consulting or advisory role with Merck Serono and is provided with travel, accommodations, and expenses by Genentech/Roche. The trial was funded by the National Institutes of Health.

CHICAGO – Patients with limited brain metastases treated with radiosurgery have a higher risk of cognitive decline if they then undergo whole-brain radiation therapy, researchers reported at the annual meeting of the American Society of Clinical Oncology.

The phase III North Central Cancer Treatment Group (NCCTG)/Alliance trial also found that although whole-brain radiation therapy (WBRT) roughly halved the likelihood of progression in the brain, it did not prolong survival. And quality of life was worse with its use as well.

“We recommend initial treatment with stereotactic radiation alone and close monitoring in order to better preserve cognitive function, and then reserving whole-brain radiation until the time of symptomatic progression,” senior study author Dr. Jan C. Buckner, professor of oncology at the Mayo Clinic, Rochester, Minnesota, said in a press briefing.

He ticked off a list of alternative approaches for avoiding cognitive problems in general for patients with brain tumors: “If at all possible, use either no radiation, low-dose radiation, hippocampal-sparing radiation, or a combination of radiation and memantine as a way to reduce the risk of cognitive decline because essentially, the brain does not like to be radiated.”

ASCO expert Dr. Brian Michael Alexander said, “This scenario is a pretty complex one, and one that I take a lot of time talking to my patients about.” The disconnect between local control and survival with whole-brain radiation may be due to the availability of very good salvage therapies when brain metastases recur (so that recurrence is irrelevant) or a situation wherein progressive disease outside the brain is driving mortality, he proposed.

“If [the latter] is more of the answer, then … the population of patients who are unlikely to have deaths from progression of disease outside the brain may be the only place where you find a benefit for whole-brain radiation therapy,” according to Dr. Alexander, who is also Disease Center Leader of Radiation Oncology and a physician with the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, and an assistant professor of Radiation Oncology at Harvard Medical School, both in Boston.

Given the totality of data today on the risks and benefits of this therapy, “I think the burden of proof is now switched, to say, can we prove that whole-brain radiation therapy is beneficial in a subset of patients?” he maintained, adding that the calculus may be changing with better systemic therapies, such as targeted agents for lung cancer, that may reduce brain metastases.

In their National Institutes of Health–funded trial, Dr. Buckner and colleagues studied 213 adults who had one to three cerebral metastases measuring up to 3 cm in diameter. They were randomly assigned to receive radiosurgery alone or radiosurgery followed by WBRT. Cognitive progression, the trial’s primary endpoint, was assessed with a battery of tests.

With a median follow-up of 7.2 months, the 3-month rate of cognitive progression, defined as a decline of greater than one standard deviation from baseline in any of the six tests used, was 92% in the WBRT group and 64% in the control group (P = .0007). Specifically, the former were more likely to experience declines in immediate recall (30% vs. 8%), delayed recall (51% vs. 20%), and verbal fluency (19% vs. 2%).

The overall difference in cognitive decline persisted at 6 months and there was additionally a trend at 12 months among the small subset of patients still alive. The WBRT group also had significantly worse scores for patient-reported quality of life.

The 3-month rate of failure in the central nervous system was lower for the patients given WBRT (6% vs. 25%, P less than .0001), but overall survival did not differ significantly between groups, either in the entire population or in subgroups. “In spite of imaging evidence of disease control, there was no overall impact on survival in these patients as they died of other causes,” reported Dr. Buckner.

In the session where the results were presented, invited discussant Dr. Andrew B. Lassman, the John Harris Associate Professor of Neurology and the Chief of Neuro-oncology at Columbia University Medical Center, New York, said, “I think there are other interpretations [of the findings] when placing this study in the context of other trials for brain metastases.”

“First, whole-brain radiotherapy does increase survival in the appropriate context. Second, deferring whole-brain radiotherapy leads to more rapid and more numerous recurrences of brain metastases, which also cause neurocognitive injury,” he elaborated. “Accordingly, whole-brain radiotherapy should be used in selected cases when brain metastases are a life-limiting site of disease. This is a form of precision medicine.”

Adequate assessment of any survival benefit of this therapy requires appropriate patient selection, Dr. Lassman maintained. Therefore, ongoing analysis of the trial’s results according to patients’ graded prognostic assessment (GPA) scores are eagerly awaited.

“Whole-brain radiotherapy remains a useful tool in the appropriate context that should not be discarded, but it is a crude tool with significant toxicities that is now over 60 years old. Refinements and new approaches are needed and in development,” he concluded.

Dr. Buckner disclosed that he has a consulting or advisory role with Merck Serono and is provided with travel, accommodations, and expenses by Genentech/Roche. The trial was funded by the National Institutes of Health.

Adult brain tumor survivors taking donepezil, a drug approved for the treatment of Alzheimer’s disease, showed significant improvements in the cognitive functions of memory, motor speed, and dexterity, compared with those taking a placebo. However, improvements in the primary outcome of composite cognitive function were similar for the two arms, investigators reported.

The study results were published online April 20 in the Journal of Clinical Oncology.

istock/Thinkstock

Patients with greater pretreatment deficits saw greater improvements in cognitive functioning with donepezil treatment, reported Stephen Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest School of Medicine, Winston-Salem, N.C., and associates.

“This suggests that treatment with a daily dose of donepezil can provide benefit to some adult long-term brain tumor survivors after PBI or WBI [partial- or whole-brain irradiation], particularly those with greater pretreatment cognitive impairment,” they wrote (J. Clin. Oncol. 2015 Apr. 20 [doi: 10.1200/JCO.2014.58.4508]).

The phase III trial enrolled 198 primary or metastatic brain tumor survivors who underwent fractionated PBI or WBI at least 6 months previously. Patients received either donepezil at 5 mg daily for 6 weeks, followed by 10 mg daily for 18 weeks if well tolerated, or placebo for 24 weeks. Composite cognitive scores improved for both arms and did not differ significantly. Donepezil treatment resulted in significantly greater improvements in memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016).

Donepezil was generally well tolerated, except for diarrhea in 25% of the active arm vs. 9% in the placebo arm (P = .005). The study retention rate was 74% at 24 weeks for both groups.

Although enrolled patients had a high level of cognitive impairment relative to noncancer controls, with 91% having at least one test score at least 1.5 standard deviations below the normal comparison group, scores across most measures varied widely from significantly lower to higher than the comparison group. This heterogeneity may underlie the less than significant improvement observed with the study treatment. Patients with greater cognitive deficits saw greater benefits.

“This indicates that brain tumors and their treatments, including cranial irradiation, are associated with clinically significant cognitive impairment among some but not all patients. In future studies, demonstrable cognitive impairment should be an inclusion criterion for enrollment,” Dr. Rapp and associates wrote.

Adult brain tumor survivors taking donepezil, a drug approved for the treatment of Alzheimer’s disease, showed significant improvements in the cognitive functions of memory, motor speed, and dexterity, compared with those taking a placebo. However, improvements in the primary outcome of composite cognitive function were similar for the two arms, investigators reported.

The study results were published online April 20 in the Journal of Clinical Oncology.

istock/Thinkstock

Patients with greater pretreatment deficits saw greater improvements in cognitive functioning with donepezil treatment, reported Stephen Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest School of Medicine, Winston-Salem, N.C., and associates.

“This suggests that treatment with a daily dose of donepezil can provide benefit to some adult long-term brain tumor survivors after PBI or WBI [partial- or whole-brain irradiation], particularly those with greater pretreatment cognitive impairment,” they wrote (J. Clin. Oncol. 2015 Apr. 20 [doi: 10.1200/JCO.2014.58.4508]).

The phase III trial enrolled 198 primary or metastatic brain tumor survivors who underwent fractionated PBI or WBI at least 6 months previously. Patients received either donepezil at 5 mg daily for 6 weeks, followed by 10 mg daily for 18 weeks if well tolerated, or placebo for 24 weeks. Composite cognitive scores improved for both arms and did not differ significantly. Donepezil treatment resulted in significantly greater improvements in memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016).

Donepezil was generally well tolerated, except for diarrhea in 25% of the active arm vs. 9% in the placebo arm (P = .005). The study retention rate was 74% at 24 weeks for both groups.

Although enrolled patients had a high level of cognitive impairment relative to noncancer controls, with 91% having at least one test score at least 1.5 standard deviations below the normal comparison group, scores across most measures varied widely from significantly lower to higher than the comparison group. This heterogeneity may underlie the less than significant improvement observed with the study treatment. Patients with greater cognitive deficits saw greater benefits.

“This indicates that brain tumors and their treatments, including cranial irradiation, are associated with clinically significant cognitive impairment among some but not all patients. In future studies, demonstrable cognitive impairment should be an inclusion criterion for enrollment,” Dr. Rapp and associates wrote.

Adult brain tumor survivors taking donepezil, a drug approved for the treatment of Alzheimer’s disease, showed significant improvements in the cognitive functions of memory, motor speed, and dexterity, compared with those taking a placebo. However, improvements in the primary outcome of composite cognitive function were similar for the two arms, investigators reported.

The study results were published online April 20 in the Journal of Clinical Oncology.

istock/Thinkstock

Patients with greater pretreatment deficits saw greater improvements in cognitive functioning with donepezil treatment, reported Stephen Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest School of Medicine, Winston-Salem, N.C., and associates.

“This suggests that treatment with a daily dose of donepezil can provide benefit to some adult long-term brain tumor survivors after PBI or WBI [partial- or whole-brain irradiation], particularly those with greater pretreatment cognitive impairment,” they wrote (J. Clin. Oncol. 2015 Apr. 20 [doi: 10.1200/JCO.2014.58.4508]).

The phase III trial enrolled 198 primary or metastatic brain tumor survivors who underwent fractionated PBI or WBI at least 6 months previously. Patients received either donepezil at 5 mg daily for 6 weeks, followed by 10 mg daily for 18 weeks if well tolerated, or placebo for 24 weeks. Composite cognitive scores improved for both arms and did not differ significantly. Donepezil treatment resulted in significantly greater improvements in memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016).

Donepezil was generally well tolerated, except for diarrhea in 25% of the active arm vs. 9% in the placebo arm (P = .005). The study retention rate was 74% at 24 weeks for both groups.

Although enrolled patients had a high level of cognitive impairment relative to noncancer controls, with 91% having at least one test score at least 1.5 standard deviations below the normal comparison group, scores across most measures varied widely from significantly lower to higher than the comparison group. This heterogeneity may underlie the less than significant improvement observed with the study treatment. Patients with greater cognitive deficits saw greater benefits.

“This indicates that brain tumors and their treatments, including cranial irradiation, are associated with clinically significant cognitive impairment among some but not all patients. In future studies, demonstrable cognitive impairment should be an inclusion criterion for enrollment,” Dr. Rapp and associates wrote.

The Food and Drug Administration has approved dinutuximab as part of a multimodality regimen, including surgery, chemotherapy, and radiation therapy, for pediatric patients with high-risk neuroblastoma.

The drug “marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in the March 10 FDA announcement.

Dinutuximab is a chimeric monoclonal antibody that targets GD2, a glycolipid on the surface of tumor cells, according to the manufacturer, United Therapeutics.

The FDA granted approval based on a clinical trial of 226 pediatric participants with high-risk neuroblastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Three years after being randomly assigned to receive either isotretinoin or dinutuximab in combination with interleukin-2 and granulocyte macrophage colony-stimulating factor, 63% of participants receiving the combination were alive and free of tumor growth or recurrence, compared with 46% of participants treated with isotretinoin alone.

In an updated analysis, 73% of participants who received the combination were alive, compared with 58% of those receiving isotretinoin alone, the FDA said in the announcement.

The most common side effects were severe pain, fever, low platelet counts, infusion reactions, low blood pressure, hyponatremia, elevated liver enzymes, anemia, vomiting, diarrhea, low potassium levels in the blood, capillary leak syndrome, neutropenia and lymphopenia, hives, and low blood calcium levels, the statement said.

The drug carries a boxed warning that the drug can irritate nerve cells, causing severe pain that requires treatment with intravenous narcotics, and can cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Dinutuximab may also cause other serious side effects, including infections, eye problems, electrolyte abnormalities, and bone marrow suppression.

The FDA granted approval of dinutuximab, to be marketed as Unituxin, following a priority review and orphan product designation.

[email protected]
On Twitter @nikolaideslaura

The Food and Drug Administration has approved dinutuximab as part of a multimodality regimen, including surgery, chemotherapy, and radiation therapy, for pediatric patients with high-risk neuroblastoma.

The drug “marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in the March 10 FDA announcement.

Dinutuximab is a chimeric monoclonal antibody that targets GD2, a glycolipid on the surface of tumor cells, according to the manufacturer, United Therapeutics.

The FDA granted approval based on a clinical trial of 226 pediatric participants with high-risk neuroblastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Three years after being randomly assigned to receive either isotretinoin or dinutuximab in combination with interleukin-2 and granulocyte macrophage colony-stimulating factor, 63% of participants receiving the combination were alive and free of tumor growth or recurrence, compared with 46% of participants treated with isotretinoin alone.

In an updated analysis, 73% of participants who received the combination were alive, compared with 58% of those receiving isotretinoin alone, the FDA said in the announcement.

The most common side effects were severe pain, fever, low platelet counts, infusion reactions, low blood pressure, hyponatremia, elevated liver enzymes, anemia, vomiting, diarrhea, low potassium levels in the blood, capillary leak syndrome, neutropenia and lymphopenia, hives, and low blood calcium levels, the statement said.

The drug carries a boxed warning that the drug can irritate nerve cells, causing severe pain that requires treatment with intravenous narcotics, and can cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Dinutuximab may also cause other serious side effects, including infections, eye problems, electrolyte abnormalities, and bone marrow suppression.

The FDA granted approval of dinutuximab, to be marketed as Unituxin, following a priority review and orphan product designation.

[email protected]
On Twitter @nikolaideslaura

The Food and Drug Administration has approved dinutuximab as part of a multimodality regimen, including surgery, chemotherapy, and radiation therapy, for pediatric patients with high-risk neuroblastoma.

The drug “marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in the March 10 FDA announcement.

Dinutuximab is a chimeric monoclonal antibody that targets GD2, a glycolipid on the surface of tumor cells, according to the manufacturer, United Therapeutics.

The FDA granted approval based on a clinical trial of 226 pediatric participants with high-risk neuroblastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Three years after being randomly assigned to receive either isotretinoin or dinutuximab in combination with interleukin-2 and granulocyte macrophage colony-stimulating factor, 63% of participants receiving the combination were alive and free of tumor growth or recurrence, compared with 46% of participants treated with isotretinoin alone.

In an updated analysis, 73% of participants who received the combination were alive, compared with 58% of those receiving isotretinoin alone, the FDA said in the announcement.

The most common side effects were severe pain, fever, low platelet counts, infusion reactions, low blood pressure, hyponatremia, elevated liver enzymes, anemia, vomiting, diarrhea, low potassium levels in the blood, capillary leak syndrome, neutropenia and lymphopenia, hives, and low blood calcium levels, the statement said.

The drug carries a boxed warning that the drug can irritate nerve cells, causing severe pain that requires treatment with intravenous narcotics, and can cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Dinutuximab may also cause other serious side effects, including infections, eye problems, electrolyte abnormalities, and bone marrow suppression.

The FDA granted approval of dinutuximab, to be marketed as Unituxin, following a priority review and orphan product designation.

[email protected]
On Twitter @nikolaideslaura

BOSTON – The risk for cognitive decline following cancer treatment varies by both cancer and therapy types, and can range from subtle changes to severe deficits, according to a researcher.

Patients who are older, have lower cognitive reserves, or have comorbidities such as cardiovascular disease or diabetes are at risk for cognitive problems following cancer treatment, said Tim A. Ahles, Ph.D., director of the Neurocognitive Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York.

“I think it’s important that we identify these modifiable risk factors for intervention, and some of the nonmodifiable risk factors that inform decision making,” he said at the Palliative Care in Oncology Symposium.

“When we talk about cognitive function, we’re really talking about how does cancer and cancer treatment impact on memory, concentration, executive function, or ability to multitask, the speed at which we process information,” he said.

Oncologists have known for decades that brain tumors and their treatment have a negative effect on cognitive function, particularly among children under 5 years of age, whose developing brains are sensitive to treatments such as chemotherapy, surgery, radiation, and high-dose steroids.

There is also a dose-response effect, with high-dose chemotherapy such as ablative regimens used for bone-marrow transplantation being associated with higher probability of cognitive problems.

Dr. Ahles noted that about two-thirds of adult survivors of childhood cancers develop chronic illnesses within 30 years of diagnosis, including cardiac and pulmonary disease, and diabetes and endocrine dysfunction.

“It turns out they’re also at higher risk for cognitive issues,” including white matter abnormalities and microvascular stroke, he said.

The population of survivors of brain tumors and childhood cancers is dwarfed, however, by the large and growing population of breast, colorectal, lung, and prostate cancer patients who are diagnosed every year and exposed to adjuvant therapies, he added.

Aging and cognitive reserve

Evidence from breast cancer studies has shown that about 20%-25% of patients have lower than expected cognitive functioning – based on age, education, occupation, and other factors – before they embark on adjuvant therapy.

“That’s actually a risk factor for posttreatment cognitive decline, so there’s something that’s already going on that’s disrupting the cognitive information-processing system before we even start adjuvant treatment that may be critically important in terms of their outcomes as survivors,” Dr. Ahles said.

A significant subset of women in longitudinal studies of breast cancer survivors – about 15%-30% – experience long-term posttreatment cognitive problems, making it imperative for researchers and clinicians to identify risk factors for persistent cognitive decline, he said.

There is evidence to suggest that cancer treatments may interplay with biologic factors at the cellular level to increase the risk for cognitive loss. For example, aging is associated with reduction in brain volume, decrease in white matter integrity, and decreases in vascularization and neurotransmitter activity.

The effects of age on the brain are attenuated, however, among patients with higher cognitive reserves, defined as a combination of innate and developed cognitive capacity. Cognitive reserve is influenced by a number of factors, including genetics, education, occupational attainment, and lifestyle.

High cognitive reserve has been associated with later onset of Alzheimer’s disease symptoms and smaller changes in cognitive function with normal aging or following a brain injury, Dr. Ahles noted.

In a longitudinal study of cognitive changes associated with adjuvant therapy for breast cancer, Dr. Ahles and colleagues found that both age and pretreatment cognitive reserve were related to posttreatment decline in processing speed in women exposed to chemotherapy, compared with those who did not have chemotherapy or with healthy controls. In addition, chemotherapy had a short-term impact on verbal ability. The authors found evidence to suggest the patterns they saw may be related to the combination of chemotherapy and tamoxifen.

Part of the difficulty of studying cognitive decline among older patients is the higher prevalence of changes associated with aging. Dr. Ahles pointed to a French longitudinal study of women over 65 being treated for breast cancer, in which investigators found that 41% of the study population had cognitive impairment before starting on adjuvant therapy.

Older adults may be more frail, with diminished biological reserves and lower resistance to stressors caused by “cumulative declines across a variety of physiological systems making you more vulnerable to adverse events,” Dr. Ahles said.

Aging and genetics

Genes associated with cognitive aging are also risk factors for posttreatment cognitive decline, notably the genetic variants of APOE, including the epsilon 4 (APOE-e4) allele linked to increased risk for early-onset Alzheimer’s disease.

Dr. Ahles and colleagues had previously shown that APOE-e4 may be a biomarker for increased risk for chemotherapy-induced cognitive decline. The adverse effects of APOE-e4 appear to be mitigated somewhat by smoking, because it may correct for a deficit in nicotinic receptor density and dopamine levels in carriers.

Another genetic factor linked to postchemotherapy cognitive decline is the Val158Met polymorphism of the gene encoding for Catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine. Patients with this polymorphism have rapid dopamine metabolism, resulting in reduced dopamine activity.

These findings point to potential molecular mechanisms for cognitive changes associated with chemotherapy, and suggest that therapies targeted at neurotransmitter systems may ameliorate the effect, Dr. Ahles said.

He noted that animal studies have shown that fluoxetine (Prozac) prevents deficits in behavior and hippocampal function associated with 5-fluourauracil (5-FU), and that nicotine patches have been shown to improve cognitive functioning in patients with mild cognitive impairment.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

BOSTON – The risk for cognitive decline following cancer treatment varies by both cancer and therapy types, and can range from subtle changes to severe deficits, according to a researcher.

Patients who are older, have lower cognitive reserves, or have comorbidities such as cardiovascular disease or diabetes are at risk for cognitive problems following cancer treatment, said Tim A. Ahles, Ph.D., director of the Neurocognitive Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York.

“I think it’s important that we identify these modifiable risk factors for intervention, and some of the nonmodifiable risk factors that inform decision making,” he said at the Palliative Care in Oncology Symposium.

“When we talk about cognitive function, we’re really talking about how does cancer and cancer treatment impact on memory, concentration, executive function, or ability to multitask, the speed at which we process information,” he said.

Oncologists have known for decades that brain tumors and their treatment have a negative effect on cognitive function, particularly among children under 5 years of age, whose developing brains are sensitive to treatments such as chemotherapy, surgery, radiation, and high-dose steroids.

There is also a dose-response effect, with high-dose chemotherapy such as ablative regimens used for bone-marrow transplantation being associated with higher probability of cognitive problems.

Dr. Ahles noted that about two-thirds of adult survivors of childhood cancers develop chronic illnesses within 30 years of diagnosis, including cardiac and pulmonary disease, and diabetes and endocrine dysfunction.

“It turns out they’re also at higher risk for cognitive issues,” including white matter abnormalities and microvascular stroke, he said.

The population of survivors of brain tumors and childhood cancers is dwarfed, however, by the large and growing population of breast, colorectal, lung, and prostate cancer patients who are diagnosed every year and exposed to adjuvant therapies, he added.

Aging and cognitive reserve

Evidence from breast cancer studies has shown that about 20%-25% of patients have lower than expected cognitive functioning – based on age, education, occupation, and other factors – before they embark on adjuvant therapy.

“That’s actually a risk factor for posttreatment cognitive decline, so there’s something that’s already going on that’s disrupting the cognitive information-processing system before we even start adjuvant treatment that may be critically important in terms of their outcomes as survivors,” Dr. Ahles said.

A significant subset of women in longitudinal studies of breast cancer survivors – about 15%-30% – experience long-term posttreatment cognitive problems, making it imperative for researchers and clinicians to identify risk factors for persistent cognitive decline, he said.

There is evidence to suggest that cancer treatments may interplay with biologic factors at the cellular level to increase the risk for cognitive loss. For example, aging is associated with reduction in brain volume, decrease in white matter integrity, and decreases in vascularization and neurotransmitter activity.

The effects of age on the brain are attenuated, however, among patients with higher cognitive reserves, defined as a combination of innate and developed cognitive capacity. Cognitive reserve is influenced by a number of factors, including genetics, education, occupational attainment, and lifestyle.

High cognitive reserve has been associated with later onset of Alzheimer’s disease symptoms and smaller changes in cognitive function with normal aging or following a brain injury, Dr. Ahles noted.

In a longitudinal study of cognitive changes associated with adjuvant therapy for breast cancer, Dr. Ahles and colleagues found that both age and pretreatment cognitive reserve were related to posttreatment decline in processing speed in women exposed to chemotherapy, compared with those who did not have chemotherapy or with healthy controls. In addition, chemotherapy had a short-term impact on verbal ability. The authors found evidence to suggest the patterns they saw may be related to the combination of chemotherapy and tamoxifen.

Part of the difficulty of studying cognitive decline among older patients is the higher prevalence of changes associated with aging. Dr. Ahles pointed to a French longitudinal study of women over 65 being treated for breast cancer, in which investigators found that 41% of the study population had cognitive impairment before starting on adjuvant therapy.

Older adults may be more frail, with diminished biological reserves and lower resistance to stressors caused by “cumulative declines across a variety of physiological systems making you more vulnerable to adverse events,” Dr. Ahles said.

Aging and genetics

Genes associated with cognitive aging are also risk factors for posttreatment cognitive decline, notably the genetic variants of APOE, including the epsilon 4 (APOE-e4) allele linked to increased risk for early-onset Alzheimer’s disease.

Dr. Ahles and colleagues had previously shown that APOE-e4 may be a biomarker for increased risk for chemotherapy-induced cognitive decline. The adverse effects of APOE-e4 appear to be mitigated somewhat by smoking, because it may correct for a deficit in nicotinic receptor density and dopamine levels in carriers.

Another genetic factor linked to postchemotherapy cognitive decline is the Val158Met polymorphism of the gene encoding for Catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine. Patients with this polymorphism have rapid dopamine metabolism, resulting in reduced dopamine activity.

These findings point to potential molecular mechanisms for cognitive changes associated with chemotherapy, and suggest that therapies targeted at neurotransmitter systems may ameliorate the effect, Dr. Ahles said.

He noted that animal studies have shown that fluoxetine (Prozac) prevents deficits in behavior and hippocampal function associated with 5-fluourauracil (5-FU), and that nicotine patches have been shown to improve cognitive functioning in patients with mild cognitive impairment.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

BOSTON – The risk for cognitive decline following cancer treatment varies by both cancer and therapy types, and can range from subtle changes to severe deficits, according to a researcher.

Patients who are older, have lower cognitive reserves, or have comorbidities such as cardiovascular disease or diabetes are at risk for cognitive problems following cancer treatment, said Tim A. Ahles, Ph.D., director of the Neurocognitive Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York.

“I think it’s important that we identify these modifiable risk factors for intervention, and some of the nonmodifiable risk factors that inform decision making,” he said at the Palliative Care in Oncology Symposium.

“When we talk about cognitive function, we’re really talking about how does cancer and cancer treatment impact on memory, concentration, executive function, or ability to multitask, the speed at which we process information,” he said.

Oncologists have known for decades that brain tumors and their treatment have a negative effect on cognitive function, particularly among children under 5 years of age, whose developing brains are sensitive to treatments such as chemotherapy, surgery, radiation, and high-dose steroids.

There is also a dose-response effect, with high-dose chemotherapy such as ablative regimens used for bone-marrow transplantation being associated with higher probability of cognitive problems.

Dr. Ahles noted that about two-thirds of adult survivors of childhood cancers develop chronic illnesses within 30 years of diagnosis, including cardiac and pulmonary disease, and diabetes and endocrine dysfunction.

“It turns out they’re also at higher risk for cognitive issues,” including white matter abnormalities and microvascular stroke, he said.

The population of survivors of brain tumors and childhood cancers is dwarfed, however, by the large and growing population of breast, colorectal, lung, and prostate cancer patients who are diagnosed every year and exposed to adjuvant therapies, he added.

Aging and cognitive reserve

Evidence from breast cancer studies has shown that about 20%-25% of patients have lower than expected cognitive functioning – based on age, education, occupation, and other factors – before they embark on adjuvant therapy.

“That’s actually a risk factor for posttreatment cognitive decline, so there’s something that’s already going on that’s disrupting the cognitive information-processing system before we even start adjuvant treatment that may be critically important in terms of their outcomes as survivors,” Dr. Ahles said.

A significant subset of women in longitudinal studies of breast cancer survivors – about 15%-30% – experience long-term posttreatment cognitive problems, making it imperative for researchers and clinicians to identify risk factors for persistent cognitive decline, he said.

There is evidence to suggest that cancer treatments may interplay with biologic factors at the cellular level to increase the risk for cognitive loss. For example, aging is associated with reduction in brain volume, decrease in white matter integrity, and decreases in vascularization and neurotransmitter activity.

The effects of age on the brain are attenuated, however, among patients with higher cognitive reserves, defined as a combination of innate and developed cognitive capacity. Cognitive reserve is influenced by a number of factors, including genetics, education, occupational attainment, and lifestyle.

High cognitive reserve has been associated with later onset of Alzheimer’s disease symptoms and smaller changes in cognitive function with normal aging or following a brain injury, Dr. Ahles noted.

In a longitudinal study of cognitive changes associated with adjuvant therapy for breast cancer, Dr. Ahles and colleagues found that both age and pretreatment cognitive reserve were related to posttreatment decline in processing speed in women exposed to chemotherapy, compared with those who did not have chemotherapy or with healthy controls. In addition, chemotherapy had a short-term impact on verbal ability. The authors found evidence to suggest the patterns they saw may be related to the combination of chemotherapy and tamoxifen.

Part of the difficulty of studying cognitive decline among older patients is the higher prevalence of changes associated with aging. Dr. Ahles pointed to a French longitudinal study of women over 65 being treated for breast cancer, in which investigators found that 41% of the study population had cognitive impairment before starting on adjuvant therapy.

Older adults may be more frail, with diminished biological reserves and lower resistance to stressors caused by “cumulative declines across a variety of physiological systems making you more vulnerable to adverse events,” Dr. Ahles said.

Aging and genetics

Genes associated with cognitive aging are also risk factors for posttreatment cognitive decline, notably the genetic variants of APOE, including the epsilon 4 (APOE-e4) allele linked to increased risk for early-onset Alzheimer’s disease.

Dr. Ahles and colleagues had previously shown that APOE-e4 may be a biomarker for increased risk for chemotherapy-induced cognitive decline. The adverse effects of APOE-e4 appear to be mitigated somewhat by smoking, because it may correct for a deficit in nicotinic receptor density and dopamine levels in carriers.

Another genetic factor linked to postchemotherapy cognitive decline is the Val158Met polymorphism of the gene encoding for Catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine. Patients with this polymorphism have rapid dopamine metabolism, resulting in reduced dopamine activity.

These findings point to potential molecular mechanisms for cognitive changes associated with chemotherapy, and suggest that therapies targeted at neurotransmitter systems may ameliorate the effect, Dr. Ahles said.

He noted that animal studies have shown that fluoxetine (Prozac) prevents deficits in behavior and hippocampal function associated with 5-fluourauracil (5-FU), and that nicotine patches have been shown to improve cognitive functioning in patients with mild cognitive impairment.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

BALTIMORE –Aggressive decompression dramatically improved survival in patients who had trapped ventricle syndrome as a result of tumor or intracerebral hemorrhage in a retrospective study.

Overall mortality in the cohort was 70% among those who had no decompression, Dr. Gabriel L. Pagani-Estevez said at the annual meeting of the American Neurological Association. But it dropped to 19% among those who underwent some form of decompression therapy. Even after controlling for confounding factors like age, etiology, and hemorrhage volume, decompression remained a significant independent predictor of survival, said Dr. Pagani-Estevez, a neurology resident at the Mayo Clinic, Rochester, Minn.

Despite all the methodological issues inherent in a retrospective study, the findings “provide at least a suggestion that neurosurgical intervention can markedly reduce mortality in trapped ventricle syndrome,” he said. “Now, research needs to clarify the ideal intervention, the effect of decompression on functional outcome, and which patients might derive the most benefit from treatment.”

The cohort comprised 392 patients who developed ventricular trapping and were treated during 2002-2010. They were a mean of 58 years old. Most (223) were not on anticoagulation therapy. A total of 80 patients were taking aspirin, and the remainder were taking other anticoagulants. The median midline shift was about 10 mm.

Trapping was caused by a tumor in 177 patients. Other etiologies included intracerebral hemorrhage (80), subdural hematoma (55), trauma (26), and stroke (18). Unspecified causes made up the remainder.

The left lateral ventricle was most often involved (176). The right lateral ventricle was trapped in 159 patients and both were involved in 32. Thirteen patients had a trapped fourth ventricle, and 12 had unspecified trapping.

Some kind of decompression procedure was performed on 221 patients. These included craniotomy (126), craniectomy (26), external ventricular drain (30), ventricular-peritoneal shunt (23), and endoscopic septum pellucidum fenestration (16).

Comparisons showed significantly decreased mortality for intervention vs. nonintervention in groups with various causes of ventricular trapping: intracerebral hemorrhage (48% vs. 95%), tumor (12% vs. 47%), and subdural hematoma (20% vs. 90%).

There were nonsignificant declines in mortality among patients who underwent intervention for ventricular trapping caused by trauma or ischemic stroke, but the number of patients in those subgroups were small, which probably confounded the results, Dr. Pagani-Estevez said.

He then conducted a multivariate analysis to determine patient characteristics that might have contributed to survival. Patients who had a decompression procedure were 87% less likely to die than were those who had not – a highly significant finding (P = .0001). A midline shift conferred a slight increase in the risk of death, while having intracerebral hemorrhage as the trapping etiology increased the risk fourfold.

Trapped ventricle carries a notoriously poor prognosis, said Dr. Alejandro A. Rabinstein, a coauthor on the study. “By the time you develop it, it’s a very bad situation, so whatever way you can achieve decompression may improve the situation,” said Dr. Rabinstein, a critical care neurologist who is also at the Mayo Clinic in Rochester. “If you don’t think the patient has enough left to merit the intervention, then you just don’t do it. But despite that limitation, if you think the patient can recover some function, it’s appropriate. An intervention will make patients survive way more often than no intervention. Without something, though, the prospect of survival is bleak.”

Neither Dr. Pagani-Estevez nor Dr. Rabinstein had any financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE –Aggressive decompression dramatically improved survival in patients who had trapped ventricle syndrome as a result of tumor or intracerebral hemorrhage in a retrospective study.

Overall mortality in the cohort was 70% among those who had no decompression, Dr. Gabriel L. Pagani-Estevez said at the annual meeting of the American Neurological Association. But it dropped to 19% among those who underwent some form of decompression therapy. Even after controlling for confounding factors like age, etiology, and hemorrhage volume, decompression remained a significant independent predictor of survival, said Dr. Pagani-Estevez, a neurology resident at the Mayo Clinic, Rochester, Minn.

Despite all the methodological issues inherent in a retrospective study, the findings “provide at least a suggestion that neurosurgical intervention can markedly reduce mortality in trapped ventricle syndrome,” he said. “Now, research needs to clarify the ideal intervention, the effect of decompression on functional outcome, and which patients might derive the most benefit from treatment.”

The cohort comprised 392 patients who developed ventricular trapping and were treated during 2002-2010. They were a mean of 58 years old. Most (223) were not on anticoagulation therapy. A total of 80 patients were taking aspirin, and the remainder were taking other anticoagulants. The median midline shift was about 10 mm.

Trapping was caused by a tumor in 177 patients. Other etiologies included intracerebral hemorrhage (80), subdural hematoma (55), trauma (26), and stroke (18). Unspecified causes made up the remainder.

The left lateral ventricle was most often involved (176). The right lateral ventricle was trapped in 159 patients and both were involved in 32. Thirteen patients had a trapped fourth ventricle, and 12 had unspecified trapping.

Some kind of decompression procedure was performed on 221 patients. These included craniotomy (126), craniectomy (26), external ventricular drain (30), ventricular-peritoneal shunt (23), and endoscopic septum pellucidum fenestration (16).

Comparisons showed significantly decreased mortality for intervention vs. nonintervention in groups with various causes of ventricular trapping: intracerebral hemorrhage (48% vs. 95%), tumor (12% vs. 47%), and subdural hematoma (20% vs. 90%).

There were nonsignificant declines in mortality among patients who underwent intervention for ventricular trapping caused by trauma or ischemic stroke, but the number of patients in those subgroups were small, which probably confounded the results, Dr. Pagani-Estevez said.

He then conducted a multivariate analysis to determine patient characteristics that might have contributed to survival. Patients who had a decompression procedure were 87% less likely to die than were those who had not – a highly significant finding (P = .0001). A midline shift conferred a slight increase in the risk of death, while having intracerebral hemorrhage as the trapping etiology increased the risk fourfold.

Trapped ventricle carries a notoriously poor prognosis, said Dr. Alejandro A. Rabinstein, a coauthor on the study. “By the time you develop it, it’s a very bad situation, so whatever way you can achieve decompression may improve the situation,” said Dr. Rabinstein, a critical care neurologist who is also at the Mayo Clinic in Rochester. “If you don’t think the patient has enough left to merit the intervention, then you just don’t do it. But despite that limitation, if you think the patient can recover some function, it’s appropriate. An intervention will make patients survive way more often than no intervention. Without something, though, the prospect of survival is bleak.”

Neither Dr. Pagani-Estevez nor Dr. Rabinstein had any financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE –Aggressive decompression dramatically improved survival in patients who had trapped ventricle syndrome as a result of tumor or intracerebral hemorrhage in a retrospective study.

Overall mortality in the cohort was 70% among those who had no decompression, Dr. Gabriel L. Pagani-Estevez said at the annual meeting of the American Neurological Association. But it dropped to 19% among those who underwent some form of decompression therapy. Even after controlling for confounding factors like age, etiology, and hemorrhage volume, decompression remained a significant independent predictor of survival, said Dr. Pagani-Estevez, a neurology resident at the Mayo Clinic, Rochester, Minn.

Despite all the methodological issues inherent in a retrospective study, the findings “provide at least a suggestion that neurosurgical intervention can markedly reduce mortality in trapped ventricle syndrome,” he said. “Now, research needs to clarify the ideal intervention, the effect of decompression on functional outcome, and which patients might derive the most benefit from treatment.”

The cohort comprised 392 patients who developed ventricular trapping and were treated during 2002-2010. They were a mean of 58 years old. Most (223) were not on anticoagulation therapy. A total of 80 patients were taking aspirin, and the remainder were taking other anticoagulants. The median midline shift was about 10 mm.

Trapping was caused by a tumor in 177 patients. Other etiologies included intracerebral hemorrhage (80), subdural hematoma (55), trauma (26), and stroke (18). Unspecified causes made up the remainder.

The left lateral ventricle was most often involved (176). The right lateral ventricle was trapped in 159 patients and both were involved in 32. Thirteen patients had a trapped fourth ventricle, and 12 had unspecified trapping.

Some kind of decompression procedure was performed on 221 patients. These included craniotomy (126), craniectomy (26), external ventricular drain (30), ventricular-peritoneal shunt (23), and endoscopic septum pellucidum fenestration (16).

Comparisons showed significantly decreased mortality for intervention vs. nonintervention in groups with various causes of ventricular trapping: intracerebral hemorrhage (48% vs. 95%), tumor (12% vs. 47%), and subdural hematoma (20% vs. 90%).

There were nonsignificant declines in mortality among patients who underwent intervention for ventricular trapping caused by trauma or ischemic stroke, but the number of patients in those subgroups were small, which probably confounded the results, Dr. Pagani-Estevez said.

He then conducted a multivariate analysis to determine patient characteristics that might have contributed to survival. Patients who had a decompression procedure were 87% less likely to die than were those who had not – a highly significant finding (P = .0001). A midline shift conferred a slight increase in the risk of death, while having intracerebral hemorrhage as the trapping etiology increased the risk fourfold.

Trapped ventricle carries a notoriously poor prognosis, said Dr. Alejandro A. Rabinstein, a coauthor on the study. “By the time you develop it, it’s a very bad situation, so whatever way you can achieve decompression may improve the situation,” said Dr. Rabinstein, a critical care neurologist who is also at the Mayo Clinic in Rochester. “If you don’t think the patient has enough left to merit the intervention, then you just don’t do it. But despite that limitation, if you think the patient can recover some function, it’s appropriate. An intervention will make patients survive way more often than no intervention. Without something, though, the prospect of survival is bleak.”

Neither Dr. Pagani-Estevez nor Dr. Rabinstein had any financial disclosures.

[email protected]

On Twitter @alz_gal

Last month, the Food and Drug Administration announced the latest steps it is taking to advance the use of personalized medicine.

First, the agency finalized guidance on the development of companion diagnostics. Second, it signaled its intent to begin oversight of certain laboratory developed tests (LDTs), tests that are designed, manufactured, and used within a single laboratory.

The guidance, initially issued as a draft in July 2011, offers the agency’s thinking on its expectations on the development of companion diagnostics. No substantive changes were made to the final guidance document from its draft version, agency officials said.

"When drug companies develop therapies that will only work on specific subpopulations, it’s important those therapies are approved with a diagnostic test that the FDA knows is accurate and reliable and patients and their physicians can count on," FDA Commissioner Dr. Margaret Hamburg said during a press teleconference.

The agency also revealed its initial thoughts on how it will regulate LDTs in a letter to Congress. The FDA is required to let Congress know 60 days prior to the issuance of draft and final guidance. The forthcoming draft represents a change in how the agency is approaching LDTs.

"The FDA has historically exercised enforcement discretion over LDTs, meaning the agency generally did not enforce applicable regulatory requirements on the tests because they were generally considered lower risk and used on a limited basis within a given institution," Dr. Hamburg said. "Today, they may be marketed and used more broadly and compete with FDA-approved tests without clinical studies to support their use. The deeper concern is about physicians and patients making critical health decisions based on diagnostic tests that have generally not been reviewed by the FDA. Without premarket review by the agency, patients, their health care providers, or the FDA itself cannot be assured those tests are accurate and reliable."

Dr. Hamburg said the agency plans to enforce premarket review requirements for higher-risk LDTs, "including those used to determine medical treatment and that have the same intended use of FDA-approved and FDA-cleared companion diagnostics currently on the market."

The agency’s actions received praise from cancer researchers.

"The recent announcements by the FDA are aimed at providing patients and their physicians with an important level of confidence and certainty with regard to the highly complex molecular and genetic information that these diagnostic tests are determining," American Association for Cancer Research President Dr. Carlos L. Arteaga said in a statement. "As an organization that represents the entire continuum of research, from the laboratory to the clinic, including the clinical researchers and physician-scientists engaged in cancer patient care, the AACR looks forward to continuing to engage with the FDA to ensure that the molecular and genetic diagnostic tests that are being utilized by physicians and patients are based on solidly supported scientific evidence."

Many in the health care community, particularly those in the oncology community, are looking at how best to use personalized medicine as a means of achieving better treatment outcomes and controlling costs of health care.

[email protected]

Last month, the Food and Drug Administration announced the latest steps it is taking to advance the use of personalized medicine.

First, the agency finalized guidance on the development of companion diagnostics. Second, it signaled its intent to begin oversight of certain laboratory developed tests (LDTs), tests that are designed, manufactured, and used within a single laboratory.

The guidance, initially issued as a draft in July 2011, offers the agency’s thinking on its expectations on the development of companion diagnostics. No substantive changes were made to the final guidance document from its draft version, agency officials said.

"When drug companies develop therapies that will only work on specific subpopulations, it’s important those therapies are approved with a diagnostic test that the FDA knows is accurate and reliable and patients and their physicians can count on," FDA Commissioner Dr. Margaret Hamburg said during a press teleconference.

The agency also revealed its initial thoughts on how it will regulate LDTs in a letter to Congress. The FDA is required to let Congress know 60 days prior to the issuance of draft and final guidance. The forthcoming draft represents a change in how the agency is approaching LDTs.

"The FDA has historically exercised enforcement discretion over LDTs, meaning the agency generally did not enforce applicable regulatory requirements on the tests because they were generally considered lower risk and used on a limited basis within a given institution," Dr. Hamburg said. "Today, they may be marketed and used more broadly and compete with FDA-approved tests without clinical studies to support their use. The deeper concern is about physicians and patients making critical health decisions based on diagnostic tests that have generally not been reviewed by the FDA. Without premarket review by the agency, patients, their health care providers, or the FDA itself cannot be assured those tests are accurate and reliable."

Dr. Hamburg said the agency plans to enforce premarket review requirements for higher-risk LDTs, "including those used to determine medical treatment and that have the same intended use of FDA-approved and FDA-cleared companion diagnostics currently on the market."

The agency’s actions received praise from cancer researchers.

"The recent announcements by the FDA are aimed at providing patients and their physicians with an important level of confidence and certainty with regard to the highly complex molecular and genetic information that these diagnostic tests are determining," American Association for Cancer Research President Dr. Carlos L. Arteaga said in a statement. "As an organization that represents the entire continuum of research, from the laboratory to the clinic, including the clinical researchers and physician-scientists engaged in cancer patient care, the AACR looks forward to continuing to engage with the FDA to ensure that the molecular and genetic diagnostic tests that are being utilized by physicians and patients are based on solidly supported scientific evidence."

Many in the health care community, particularly those in the oncology community, are looking at how best to use personalized medicine as a means of achieving better treatment outcomes and controlling costs of health care.

[email protected]

Last month, the Food and Drug Administration announced the latest steps it is taking to advance the use of personalized medicine.

First, the agency finalized guidance on the development of companion diagnostics. Second, it signaled its intent to begin oversight of certain laboratory developed tests (LDTs), tests that are designed, manufactured, and used within a single laboratory.

The guidance, initially issued as a draft in July 2011, offers the agency’s thinking on its expectations on the development of companion diagnostics. No substantive changes were made to the final guidance document from its draft version, agency officials said.

"When drug companies develop therapies that will only work on specific subpopulations, it’s important those therapies are approved with a diagnostic test that the FDA knows is accurate and reliable and patients and their physicians can count on," FDA Commissioner Dr. Margaret Hamburg said during a press teleconference.

The agency also revealed its initial thoughts on how it will regulate LDTs in a letter to Congress. The FDA is required to let Congress know 60 days prior to the issuance of draft and final guidance. The forthcoming draft represents a change in how the agency is approaching LDTs.

"The FDA has historically exercised enforcement discretion over LDTs, meaning the agency generally did not enforce applicable regulatory requirements on the tests because they were generally considered lower risk and used on a limited basis within a given institution," Dr. Hamburg said. "Today, they may be marketed and used more broadly and compete with FDA-approved tests without clinical studies to support their use. The deeper concern is about physicians and patients making critical health decisions based on diagnostic tests that have generally not been reviewed by the FDA. Without premarket review by the agency, patients, their health care providers, or the FDA itself cannot be assured those tests are accurate and reliable."

Dr. Hamburg said the agency plans to enforce premarket review requirements for higher-risk LDTs, "including those used to determine medical treatment and that have the same intended use of FDA-approved and FDA-cleared companion diagnostics currently on the market."

The agency’s actions received praise from cancer researchers.

"The recent announcements by the FDA are aimed at providing patients and their physicians with an important level of confidence and certainty with regard to the highly complex molecular and genetic information that these diagnostic tests are determining," American Association for Cancer Research President Dr. Carlos L. Arteaga said in a statement. "As an organization that represents the entire continuum of research, from the laboratory to the clinic, including the clinical researchers and physician-scientists engaged in cancer patient care, the AACR looks forward to continuing to engage with the FDA to ensure that the molecular and genetic diagnostic tests that are being utilized by physicians and patients are based on solidly supported scientific evidence."

Many in the health care community, particularly those in the oncology community, are looking at how best to use personalized medicine as a means of achieving better treatment outcomes and controlling costs of health care.

[email protected]

The addition of bevacizumab to standard treatment did not improve survival in patients with newly diagnosed glioblastoma, and in some cases, worsened quality of life and led to cognitive decline.

Bevacizumab (Avastin) added to frontline radiation and temozolomide therapy extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, a double-blind, placebo-controlled phase III trial, Dr. Mark R. Gilbert of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates reported Feb. 19 in the New England Journal of Medicine.

Among 637 patients with centrally confirmed glioblastoma who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide, and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab. (N. Engl. J. Med. 2014; 370:699-708.)

Median overall survival data were virtually identical in a second similarly designed study, also reported Feb. 19 in the New England Journal of Medicine.

Median survival in Avaglio, which ran parallel to RTOG 0825, was 16.8 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 16.7 months in 463 patients in its radiation, temozolomide, and placebo arm, Dr. Olivier L. Chinot of Aix-Marseille University, Marseille, France, and his associates reported (N. Engl. J. Med. 2014; 370:709-22).

Median progression-free survival in Avaglio reached 10.6 months in the bevacizumab arm vs. 6.2 months in the placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

The Avaglio trial showed a benefit or maintenance of quality of life measures, but did not look at neurocognitive outcomes. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%), reported Dr. Chinot and his associates.

Both studies were presented last year at the annual meeting of the American Society of Clinical Oncology.

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. Chinot disclosed receiving financial and nonfinancial support from Roche.

[email protected]

On Twitter @NikolaidesLaura

The addition of bevacizumab to standard treatment did not improve survival in patients with newly diagnosed glioblastoma, and in some cases, worsened quality of life and led to cognitive decline.

Bevacizumab (Avastin) added to frontline radiation and temozolomide therapy extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, a double-blind, placebo-controlled phase III trial, Dr. Mark R. Gilbert of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates reported Feb. 19 in the New England Journal of Medicine.

Among 637 patients with centrally confirmed glioblastoma who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide, and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab. (N. Engl. J. Med. 2014; 370:699-708.)

Median overall survival data were virtually identical in a second similarly designed study, also reported Feb. 19 in the New England Journal of Medicine.

Median survival in Avaglio, which ran parallel to RTOG 0825, was 16.8 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 16.7 months in 463 patients in its radiation, temozolomide, and placebo arm, Dr. Olivier L. Chinot of Aix-Marseille University, Marseille, France, and his associates reported (N. Engl. J. Med. 2014; 370:709-22).

Median progression-free survival in Avaglio reached 10.6 months in the bevacizumab arm vs. 6.2 months in the placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

The Avaglio trial showed a benefit or maintenance of quality of life measures, but did not look at neurocognitive outcomes. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%), reported Dr. Chinot and his associates.

Both studies were presented last year at the annual meeting of the American Society of Clinical Oncology.

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. Chinot disclosed receiving financial and nonfinancial support from Roche.

[email protected]

On Twitter @NikolaidesLaura

The addition of bevacizumab to standard treatment did not improve survival in patients with newly diagnosed glioblastoma, and in some cases, worsened quality of life and led to cognitive decline.

Bevacizumab (Avastin) added to frontline radiation and temozolomide therapy extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, a double-blind, placebo-controlled phase III trial, Dr. Mark R. Gilbert of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates reported Feb. 19 in the New England Journal of Medicine.

Among 637 patients with centrally confirmed glioblastoma who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide, and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab. (N. Engl. J. Med. 2014; 370:699-708.)

Median overall survival data were virtually identical in a second similarly designed study, also reported Feb. 19 in the New England Journal of Medicine.

Median survival in Avaglio, which ran parallel to RTOG 0825, was 16.8 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 16.7 months in 463 patients in its radiation, temozolomide, and placebo arm, Dr. Olivier L. Chinot of Aix-Marseille University, Marseille, France, and his associates reported (N. Engl. J. Med. 2014; 370:709-22).

Median progression-free survival in Avaglio reached 10.6 months in the bevacizumab arm vs. 6.2 months in the placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

The Avaglio trial showed a benefit or maintenance of quality of life measures, but did not look at neurocognitive outcomes. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%), reported Dr. Chinot and his associates.

Both studies were presented last year at the annual meeting of the American Society of Clinical Oncology.

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. Chinot disclosed receiving financial and nonfinancial support from Roche.

[email protected]

On Twitter @NikolaidesLaura

SAN FRANCISCO – A new chemotherapy regimen of capecitabine and temozolomide was highly active against advanced treatment-resistant neuroendocrine tumors, based on the interim results of a phase II trial.

Tumors shrank in 43% of the 28 patients with various types of differentiated metastatic neuroendocrine tumors given the regimen, which is abbreviated CAPTEM. Disease stabilized in 54%.

Responses were durable, with a median progression-free survival approaching 2 years, reported lead investigator Dr. Robert Fine of the department of medicine at New York Presbyterian Hospital–Columbia University Medical Center.

"In this study, we’re seeing patients who had been given 6 months to live and are still alive 8 years after starting CAPTEM," he said in a prepared statement. "The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery."

For example, 42% of the patients with carcinoid tumors had a complete or partial response, and the others had stabilization of their disease. Median progression-free survival in this subset exceeded 31 months.

"Pituitary tumors were extraordinarily sensitive – end-stage people on respirators who were intubated with pituitary masses [compressing the spinal cord] were 100% responsive to the regimen, he said. Two of three patients had a complete response and were able to come off the ventilator and remain disease free with ongoing treatment at nearly 4 years out. The other patient had a partial response.

Toxicities were mild, and none of the patients had to be hospitalized or died as a result of the treatment, Dr. Fine commented in a press briefing before the results were presented at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland, who was the press briefing moderator, concurred that the regimen offers a new treatment option to patients who have exhausted the standard options.

"This regimen of CAPTEM vs. TEM (temozolomide) is under study now in a cooperative group trial for patients with pancreatic neuroendocrine cancer," she noted.

Dr. Fine and his team enrolled patients in the trial who had well- or moderately differentiated neuroendocrine tumors and either experienced progression despite standard therapy with high-dose octreotide (Sandostatin) or were ineligible for this treatment because of a negative octreotide scan. Other prior treatments, with the exception of the two drugs being studied, were allowed.

CAPTEM contains capecitabine (Xeloda), currently approved by the Food and Drug Administration for the treatment of breast and colorectal cancers, and temozolomide (Temodar), currently approved for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

The drugs are given in sequence to maximize efficacy, according to Dr. Fine, as the capecitabine depletes tumor thymidine stores, which dramatically potentiates the antitumor effect of the temozolomide.

Of the 28 patients, 12 had carcinoid tumors, 11 had pancreatic tumors, 3 had pituitary tumors, and 2 had medullary thyroid tumors.

The patients were treated with CAPTEM on 28-day cycles, with capecitabine alone for 9 days, both capecitabine and temozolomide for 5 days, and the next 14 days off.

Overall, 11% of patients had a complete response, 32% had a partial response, 54% had stable disease, and 3% had progressive disease. These values translated to a response rate of 43% and a clinical benefit rate of 97%.

Median progression-free survival exceeded 22 months, and median overall survival, although still maturing, exceeded 29 months.

"The toxicities were extraordinarily light," commented Dr. Fine, who disclosed that he receives research funding from Merck.

The most common grade 3 or 4 toxicities were lymphopenia (seen in 35% of patients), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).

None of the patients were hospitalized, developed opportunistic infections, or died as a result of CAPTEM treatment.

SAN FRANCISCO – A new chemotherapy regimen of capecitabine and temozolomide was highly active against advanced treatment-resistant neuroendocrine tumors, based on the interim results of a phase II trial.

Tumors shrank in 43% of the 28 patients with various types of differentiated metastatic neuroendocrine tumors given the regimen, which is abbreviated CAPTEM. Disease stabilized in 54%.

Responses were durable, with a median progression-free survival approaching 2 years, reported lead investigator Dr. Robert Fine of the department of medicine at New York Presbyterian Hospital–Columbia University Medical Center.

"In this study, we’re seeing patients who had been given 6 months to live and are still alive 8 years after starting CAPTEM," he said in a prepared statement. "The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery."

For example, 42% of the patients with carcinoid tumors had a complete or partial response, and the others had stabilization of their disease. Median progression-free survival in this subset exceeded 31 months.

"Pituitary tumors were extraordinarily sensitive – end-stage people on respirators who were intubated with pituitary masses [compressing the spinal cord] were 100% responsive to the regimen, he said. Two of three patients had a complete response and were able to come off the ventilator and remain disease free with ongoing treatment at nearly 4 years out. The other patient had a partial response.

Toxicities were mild, and none of the patients had to be hospitalized or died as a result of the treatment, Dr. Fine commented in a press briefing before the results were presented at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland, who was the press briefing moderator, concurred that the regimen offers a new treatment option to patients who have exhausted the standard options.

"This regimen of CAPTEM vs. TEM (temozolomide) is under study now in a cooperative group trial for patients with pancreatic neuroendocrine cancer," she noted.

Dr. Fine and his team enrolled patients in the trial who had well- or moderately differentiated neuroendocrine tumors and either experienced progression despite standard therapy with high-dose octreotide (Sandostatin) or were ineligible for this treatment because of a negative octreotide scan. Other prior treatments, with the exception of the two drugs being studied, were allowed.

CAPTEM contains capecitabine (Xeloda), currently approved by the Food and Drug Administration for the treatment of breast and colorectal cancers, and temozolomide (Temodar), currently approved for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

The drugs are given in sequence to maximize efficacy, according to Dr. Fine, as the capecitabine depletes tumor thymidine stores, which dramatically potentiates the antitumor effect of the temozolomide.

Of the 28 patients, 12 had carcinoid tumors, 11 had pancreatic tumors, 3 had pituitary tumors, and 2 had medullary thyroid tumors.

The patients were treated with CAPTEM on 28-day cycles, with capecitabine alone for 9 days, both capecitabine and temozolomide for 5 days, and the next 14 days off.

Overall, 11% of patients had a complete response, 32% had a partial response, 54% had stable disease, and 3% had progressive disease. These values translated to a response rate of 43% and a clinical benefit rate of 97%.

Median progression-free survival exceeded 22 months, and median overall survival, although still maturing, exceeded 29 months.

"The toxicities were extraordinarily light," commented Dr. Fine, who disclosed that he receives research funding from Merck.

The most common grade 3 or 4 toxicities were lymphopenia (seen in 35% of patients), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).

None of the patients were hospitalized, developed opportunistic infections, or died as a result of CAPTEM treatment.

SAN FRANCISCO – A new chemotherapy regimen of capecitabine and temozolomide was highly active against advanced treatment-resistant neuroendocrine tumors, based on the interim results of a phase II trial.

Tumors shrank in 43% of the 28 patients with various types of differentiated metastatic neuroendocrine tumors given the regimen, which is abbreviated CAPTEM. Disease stabilized in 54%.

Responses were durable, with a median progression-free survival approaching 2 years, reported lead investigator Dr. Robert Fine of the department of medicine at New York Presbyterian Hospital–Columbia University Medical Center.

"In this study, we’re seeing patients who had been given 6 months to live and are still alive 8 years after starting CAPTEM," he said in a prepared statement. "The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery."

For example, 42% of the patients with carcinoid tumors had a complete or partial response, and the others had stabilization of their disease. Median progression-free survival in this subset exceeded 31 months.

"Pituitary tumors were extraordinarily sensitive – end-stage people on respirators who were intubated with pituitary masses [compressing the spinal cord] were 100% responsive to the regimen, he said. Two of three patients had a complete response and were able to come off the ventilator and remain disease free with ongoing treatment at nearly 4 years out. The other patient had a partial response.

Toxicities were mild, and none of the patients had to be hospitalized or died as a result of the treatment, Dr. Fine commented in a press briefing before the results were presented at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland, who was the press briefing moderator, concurred that the regimen offers a new treatment option to patients who have exhausted the standard options.

"This regimen of CAPTEM vs. TEM (temozolomide) is under study now in a cooperative group trial for patients with pancreatic neuroendocrine cancer," she noted.

Dr. Fine and his team enrolled patients in the trial who had well- or moderately differentiated neuroendocrine tumors and either experienced progression despite standard therapy with high-dose octreotide (Sandostatin) or were ineligible for this treatment because of a negative octreotide scan. Other prior treatments, with the exception of the two drugs being studied, were allowed.

CAPTEM contains capecitabine (Xeloda), currently approved by the Food and Drug Administration for the treatment of breast and colorectal cancers, and temozolomide (Temodar), currently approved for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

The drugs are given in sequence to maximize efficacy, according to Dr. Fine, as the capecitabine depletes tumor thymidine stores, which dramatically potentiates the antitumor effect of the temozolomide.

Of the 28 patients, 12 had carcinoid tumors, 11 had pancreatic tumors, 3 had pituitary tumors, and 2 had medullary thyroid tumors.

The patients were treated with CAPTEM on 28-day cycles, with capecitabine alone for 9 days, both capecitabine and temozolomide for 5 days, and the next 14 days off.

Overall, 11% of patients had a complete response, 32% had a partial response, 54% had stable disease, and 3% had progressive disease. These values translated to a response rate of 43% and a clinical benefit rate of 97%.

Median progression-free survival exceeded 22 months, and median overall survival, although still maturing, exceeded 29 months.

"The toxicities were extraordinarily light," commented Dr. Fine, who disclosed that he receives research funding from Merck.

The most common grade 3 or 4 toxicities were lymphopenia (seen in 35% of patients), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).

None of the patients were hospitalized, developed opportunistic infections, or died as a result of CAPTEM treatment.