CNS/Brain Cancer

CHICAGO – Donepezil proved no better than placebo at improving overall cognitive function among 198 patients who had undergone partial or whole brain irradiation for brain tumors, investigators reported at the annual meeting of the American Society of Clinical Oncology.

A randomized, double-blind, multicenter phase III trial found no significant differences between donepezil (Aricept) and placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory, said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest Baptist Medical Center in Winston-Salem, N.C.

Among patients with more cognitive problems at baseline, however, there was a significant benefit in verbal memory for patients on donepezil, compared with controls (P = .005), and a trend toward preservation of motor speed and dexterity, Dr. Rapp said.

"We have to continue looking for effective treatments for cognitive symptoms in this population. It has a big impact on patients," he said.

Previous studies indicated that more than half of patients who receive partial or whole brain irradiation for tumors will have cognitive deficits, and that about 12% will develop some form of dementia. Cognitive problems have a major impact on patient quality of life, and anything clinicians can do to preserve or improve patient mental faculties is important, Dr. Rapp said.

The study was designed to test whether donepezil, an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate cognitive decline from Alzheimer’s disease, could have a similar neuroprotective effect following whole brain irradiation.

Investigators enrolled 198 patients 6 months after they received at least 30 Gy of brain irradiation. Following a baseline evaluation, patients were randomized to receive either 5-10 mg daily of oral donepezil or placebo for 24 weeks, with an interim assessment performed at 12 weeks.

The study looked at the effect of the drug on cognitive functioning and on measures of fatigue, mood, and quality of life.

The patients were assessed at baseline for cognitive function, and at 12 and 24 weeks with the Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure-modified (a measure of visual spatial ability, memory, and planning ability), Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard (a measure of dexterity and motor control).

Both study arms showed significant improvement in cognitive composite scores over baseline (P less than .01 for both), but the degree of improvement did not differ significantly between arms. Similarly, there were no significant differences between the treatment arms in any of the test domains, Dr. Rapp said.

Among patients with greater baseline cognitive deficits, as measured by a score of less than 51 on the FACT Brain subscale, there was also significant improvement over baseline but no between-group difference, he reported.

Donepezil was significantly better than placebo control in this subgroup for improvement in performance on the recognition portion of the Hopkins Verbal Learning Test, which measures verbal memory, and donepezil danced on the edge of significance at preserving motor speed and dexterity as measured by the Grooved Pegboard-Dominant Hand test but never crossed the line (P = .06), he said.

Adverse events were similar between the groups, and the patients assigned to donepezil appeared to tolerate it well, Dr. Rapp said.

Dr. Robin Grant of the Center for Clinical Brain Sciences at the University of Edinburgh, the invited discussant, said that the study was very well designed. He noted, however, "that there was no specified level of cognitive deficit at the time of [study] entry, and I think if you look at moderate to severely affected patients then you’re more likely to be able to show a change there," he said.

He added that it would be interesting to see results from the Grooved Pegboard test performed with the contralateral rather than dominant hand.

The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.

CHICAGO – Donepezil proved no better than placebo at improving overall cognitive function among 198 patients who had undergone partial or whole brain irradiation for brain tumors, investigators reported at the annual meeting of the American Society of Clinical Oncology.

A randomized, double-blind, multicenter phase III trial found no significant differences between donepezil (Aricept) and placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory, said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest Baptist Medical Center in Winston-Salem, N.C.

Among patients with more cognitive problems at baseline, however, there was a significant benefit in verbal memory for patients on donepezil, compared with controls (P = .005), and a trend toward preservation of motor speed and dexterity, Dr. Rapp said.

"We have to continue looking for effective treatments for cognitive symptoms in this population. It has a big impact on patients," he said.

Previous studies indicated that more than half of patients who receive partial or whole brain irradiation for tumors will have cognitive deficits, and that about 12% will develop some form of dementia. Cognitive problems have a major impact on patient quality of life, and anything clinicians can do to preserve or improve patient mental faculties is important, Dr. Rapp said.

The study was designed to test whether donepezil, an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate cognitive decline from Alzheimer’s disease, could have a similar neuroprotective effect following whole brain irradiation.

Investigators enrolled 198 patients 6 months after they received at least 30 Gy of brain irradiation. Following a baseline evaluation, patients were randomized to receive either 5-10 mg daily of oral donepezil or placebo for 24 weeks, with an interim assessment performed at 12 weeks.

The study looked at the effect of the drug on cognitive functioning and on measures of fatigue, mood, and quality of life.

The patients were assessed at baseline for cognitive function, and at 12 and 24 weeks with the Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure-modified (a measure of visual spatial ability, memory, and planning ability), Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard (a measure of dexterity and motor control).

Both study arms showed significant improvement in cognitive composite scores over baseline (P less than .01 for both), but the degree of improvement did not differ significantly between arms. Similarly, there were no significant differences between the treatment arms in any of the test domains, Dr. Rapp said.

Among patients with greater baseline cognitive deficits, as measured by a score of less than 51 on the FACT Brain subscale, there was also significant improvement over baseline but no between-group difference, he reported.

Donepezil was significantly better than placebo control in this subgroup for improvement in performance on the recognition portion of the Hopkins Verbal Learning Test, which measures verbal memory, and donepezil danced on the edge of significance at preserving motor speed and dexterity as measured by the Grooved Pegboard-Dominant Hand test but never crossed the line (P = .06), he said.

Adverse events were similar between the groups, and the patients assigned to donepezil appeared to tolerate it well, Dr. Rapp said.

Dr. Robin Grant of the Center for Clinical Brain Sciences at the University of Edinburgh, the invited discussant, said that the study was very well designed. He noted, however, "that there was no specified level of cognitive deficit at the time of [study] entry, and I think if you look at moderate to severely affected patients then you’re more likely to be able to show a change there," he said.

He added that it would be interesting to see results from the Grooved Pegboard test performed with the contralateral rather than dominant hand.

The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.

CHICAGO – Donepezil proved no better than placebo at improving overall cognitive function among 198 patients who had undergone partial or whole brain irradiation for brain tumors, investigators reported at the annual meeting of the American Society of Clinical Oncology.

A randomized, double-blind, multicenter phase III trial found no significant differences between donepezil (Aricept) and placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory, said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest Baptist Medical Center in Winston-Salem, N.C.

Among patients with more cognitive problems at baseline, however, there was a significant benefit in verbal memory for patients on donepezil, compared with controls (P = .005), and a trend toward preservation of motor speed and dexterity, Dr. Rapp said.

"We have to continue looking for effective treatments for cognitive symptoms in this population. It has a big impact on patients," he said.

Previous studies indicated that more than half of patients who receive partial or whole brain irradiation for tumors will have cognitive deficits, and that about 12% will develop some form of dementia. Cognitive problems have a major impact on patient quality of life, and anything clinicians can do to preserve or improve patient mental faculties is important, Dr. Rapp said.

The study was designed to test whether donepezil, an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate cognitive decline from Alzheimer’s disease, could have a similar neuroprotective effect following whole brain irradiation.

Investigators enrolled 198 patients 6 months after they received at least 30 Gy of brain irradiation. Following a baseline evaluation, patients were randomized to receive either 5-10 mg daily of oral donepezil or placebo for 24 weeks, with an interim assessment performed at 12 weeks.

The study looked at the effect of the drug on cognitive functioning and on measures of fatigue, mood, and quality of life.

The patients were assessed at baseline for cognitive function, and at 12 and 24 weeks with the Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure-modified (a measure of visual spatial ability, memory, and planning ability), Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard (a measure of dexterity and motor control).

Both study arms showed significant improvement in cognitive composite scores over baseline (P less than .01 for both), but the degree of improvement did not differ significantly between arms. Similarly, there were no significant differences between the treatment arms in any of the test domains, Dr. Rapp said.

Among patients with greater baseline cognitive deficits, as measured by a score of less than 51 on the FACT Brain subscale, there was also significant improvement over baseline but no between-group difference, he reported.

Donepezil was significantly better than placebo control in this subgroup for improvement in performance on the recognition portion of the Hopkins Verbal Learning Test, which measures verbal memory, and donepezil danced on the edge of significance at preserving motor speed and dexterity as measured by the Grooved Pegboard-Dominant Hand test but never crossed the line (P = .06), he said.

Adverse events were similar between the groups, and the patients assigned to donepezil appeared to tolerate it well, Dr. Rapp said.

Dr. Robin Grant of the Center for Clinical Brain Sciences at the University of Edinburgh, the invited discussant, said that the study was very well designed. He noted, however, "that there was no specified level of cognitive deficit at the time of [study] entry, and I think if you look at moderate to severely affected patients then you’re more likely to be able to show a change there," he said.

He added that it would be interesting to see results from the Grooved Pegboard test performed with the contralateral rather than dominant hand.

The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.

CHICAGO – Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.

Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.

Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

Median progression-free survival reached 10.7 months in the bevacizumab arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the bevacizumab arm had significantly worse neurocognitive and overall symptom scores over time.

"We feel that bevacizumab remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment," he said at a press briefing prior to his presentation.

Outcomes contrast with Avaglio study

Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the ASCO annual meeting.

The Avaglio investigators found that adding bevacizumab to radiotherapy and temozolomide "achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma," Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.

The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on bevacizumab, but did not look at neurocognitive outcomes.

Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 6.2 months in 463 patients in its radiation, temozolomide, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.

Bevacizumab misses RTOG targets

The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with temozolomide for 3 weeks followed by chemoradiation with temozolomide and either bevacizumab or placebo for 6-12 maintenance cycles.

The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on, bevacizumab. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.

In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).

(The results of the GLARIUS trial, also reported at this meeting, showed that bevacizumab combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than temozolomide chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the bevacizumab-irinotecan combination.)

As noted, in RTOG 0825, patients in the bevacizumab arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).

In contrast, patients on bevacizumab in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.

Why the differences?

Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.

Another possibility to account for the worsening neurocognitive function with bevacizumab is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.

Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as bevacizumab, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.

But although bevacizumab has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.

Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of bevacizumab to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.

"Despite these new data demonstrating its limitation, I feel very strongly that bevacizumab represents the single most important agent in glioblastoma since temozolomide, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options," Dr. Fine concluded.

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.

CHICAGO – Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.

Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.

Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

Median progression-free survival reached 10.7 months in the bevacizumab arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the bevacizumab arm had significantly worse neurocognitive and overall symptom scores over time.

"We feel that bevacizumab remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment," he said at a press briefing prior to his presentation.

Outcomes contrast with Avaglio study

Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the ASCO annual meeting.

The Avaglio investigators found that adding bevacizumab to radiotherapy and temozolomide "achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma," Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.

The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on bevacizumab, but did not look at neurocognitive outcomes.

Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 6.2 months in 463 patients in its radiation, temozolomide, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.

Bevacizumab misses RTOG targets

The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with temozolomide for 3 weeks followed by chemoradiation with temozolomide and either bevacizumab or placebo for 6-12 maintenance cycles.

The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on, bevacizumab. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.

In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).

(The results of the GLARIUS trial, also reported at this meeting, showed that bevacizumab combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than temozolomide chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the bevacizumab-irinotecan combination.)

As noted, in RTOG 0825, patients in the bevacizumab arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).

In contrast, patients on bevacizumab in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.

Why the differences?

Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.

Another possibility to account for the worsening neurocognitive function with bevacizumab is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.

Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as bevacizumab, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.

But although bevacizumab has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.

Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of bevacizumab to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.

"Despite these new data demonstrating its limitation, I feel very strongly that bevacizumab represents the single most important agent in glioblastoma since temozolomide, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options," Dr. Fine concluded.

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.

CHICAGO – Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.

Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.

Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

Median progression-free survival reached 10.7 months in the bevacizumab arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the bevacizumab arm had significantly worse neurocognitive and overall symptom scores over time.

"We feel that bevacizumab remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment," he said at a press briefing prior to his presentation.

Outcomes contrast with Avaglio study

Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the ASCO annual meeting.

The Avaglio investigators found that adding bevacizumab to radiotherapy and temozolomide "achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma," Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.

The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on bevacizumab, but did not look at neurocognitive outcomes.

Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 6.2 months in 463 patients in its radiation, temozolomide, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.

Bevacizumab misses RTOG targets

The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with temozolomide for 3 weeks followed by chemoradiation with temozolomide and either bevacizumab or placebo for 6-12 maintenance cycles.

The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on, bevacizumab. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.

In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).

(The results of the GLARIUS trial, also reported at this meeting, showed that bevacizumab combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than temozolomide chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the bevacizumab-irinotecan combination.)

As noted, in RTOG 0825, patients in the bevacizumab arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).

In contrast, patients on bevacizumab in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.

Why the differences?

Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.

Another possibility to account for the worsening neurocognitive function with bevacizumab is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.

Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as bevacizumab, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.

But although bevacizumab has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.

Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of bevacizumab to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.

"Despite these new data demonstrating its limitation, I feel very strongly that bevacizumab represents the single most important agent in glioblastoma since temozolomide, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options," Dr. Fine concluded.

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.

CHICAGO – The combination of bevacizumab and irinotecan far outshone tenozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

In the phase II GLARIUS trial, 79.6% of patients treated with bevacizumab (Avastin) and irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.

Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.

Neil Osterweil/IMNG Medical Media

A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).

"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.

The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O⁶-methylguanine-DNA methyltransferase)-unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.

Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.

All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).

The experimental arm received bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance bevacizumab at the same dose and irinotecan 125 mg/m² every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m². The standard therapy arm was given temozolomide 75 mg/m² daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m² for 5 days every 4 weeks.

In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).

In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.

The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.

"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.

Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.

The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.

CHICAGO – The combination of bevacizumab and irinotecan far outshone tenozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

In the phase II GLARIUS trial, 79.6% of patients treated with bevacizumab (Avastin) and irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.

Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.

Neil Osterweil/IMNG Medical Media

A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).

"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.

The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O⁶-methylguanine-DNA methyltransferase)-unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.

Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.

All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).

The experimental arm received bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance bevacizumab at the same dose and irinotecan 125 mg/m² every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m². The standard therapy arm was given temozolomide 75 mg/m² daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m² for 5 days every 4 weeks.

In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).

In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.

The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.

"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.

Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.

The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.

CHICAGO – The combination of bevacizumab and irinotecan far outshone tenozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

In the phase II GLARIUS trial, 79.6% of patients treated with bevacizumab (Avastin) and irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.

Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.

Neil Osterweil/IMNG Medical Media

A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).

"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.

The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O⁶-methylguanine-DNA methyltransferase)-unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.

Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.

All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).

The experimental arm received bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance bevacizumab at the same dose and irinotecan 125 mg/m² every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m². The standard therapy arm was given temozolomide 75 mg/m² daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m² for 5 days every 4 weeks.

In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).

In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.

The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.

"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.

Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.

The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.

SAN DIEGO – Medical management with sirolimus or everolimus for pediatric patients with tuberous sclerosis complex and subependymal giant cell astrocytomas is more effective and safer than surgery, researchers from the University of Cincinnati and University of California, Los Angeles, have found.

Although the benign tumors have traditionally been left to surgeons, it’s become clear in recent years that rapamycin analogs are effective, too. The question has been "which [approach] is best? Medical management "is known to be pretty mild compared to the surgery," but it’s not curative, explained lead investigator Susanne Yoon, the University of Cincinnati medical student who presented the results at the annual meeting of the American Academy of Neurology.

The team compared outcomes for 23 SEGA (subependymal giant cell astrocytoma) patients who underwent surgery, 81 who took sirolimus or everolimus, and 9 who got both. The surgery patients were diagnosed when they were about 10 years old and were followed for a median of 8.9 years; the medical patients were about 7 years old when diagnosed, and were followed for a median of 2.8 years. Boys made up the majority of both groups.

None of the children who took a rapamycin analog needed surgery; tumors shrank by more than half in 61% (45). The drugs caused infections, weight change, or hyperlipidemia in some, but only 13% (11) needed to stop the drug or go to the hospital because of side effects.

Meanwhile, surgery cured just 39% (9) of the children who got it, sometimes after two or three operations; 61% (14) of those patients had prolonged hospitalizations or were hospitalized due to postoperative complications that included intracranial hemorrhage in 8, hydrocephalus/shunt malfunction in 6, neurologic impairment, and seizures.

"Not only does medical management win in efficacy, but it also wins in the safety issues. Rapalog [rapamycin] therapy, alone or in combination, is becoming a cornerstone of tumor management" in neurocutaneous disorders, said Dr. David H. Viskochil, professor of pediatrics at the University of Utah, Salt Lake City, commenting on the study.

"Of course, there are emergent situations where you’ve just got to go in and get the tumor out; you can’t wait 3 months to see" if drugs work. "But if a child is just starting to show some symptoms and not deteriorating, then you can start with medicine first and see what happens," he said.

"The question is if you got [SEGAs] really early, would surgical cure be much more likely? The studies aren’t quite there yet," he said in an interview.

Ms. Yoon and Dr. Viskochil said they have no disclosures.

[email protected]

SAN DIEGO – Medical management with sirolimus or everolimus for pediatric patients with tuberous sclerosis complex and subependymal giant cell astrocytomas is more effective and safer than surgery, researchers from the University of Cincinnati and University of California, Los Angeles, have found.

Although the benign tumors have traditionally been left to surgeons, it’s become clear in recent years that rapamycin analogs are effective, too. The question has been "which [approach] is best? Medical management "is known to be pretty mild compared to the surgery," but it’s not curative, explained lead investigator Susanne Yoon, the University of Cincinnati medical student who presented the results at the annual meeting of the American Academy of Neurology.

The team compared outcomes for 23 SEGA (subependymal giant cell astrocytoma) patients who underwent surgery, 81 who took sirolimus or everolimus, and 9 who got both. The surgery patients were diagnosed when they were about 10 years old and were followed for a median of 8.9 years; the medical patients were about 7 years old when diagnosed, and were followed for a median of 2.8 years. Boys made up the majority of both groups.

None of the children who took a rapamycin analog needed surgery; tumors shrank by more than half in 61% (45). The drugs caused infections, weight change, or hyperlipidemia in some, but only 13% (11) needed to stop the drug or go to the hospital because of side effects.

Meanwhile, surgery cured just 39% (9) of the children who got it, sometimes after two or three operations; 61% (14) of those patients had prolonged hospitalizations or were hospitalized due to postoperative complications that included intracranial hemorrhage in 8, hydrocephalus/shunt malfunction in 6, neurologic impairment, and seizures.

"Not only does medical management win in efficacy, but it also wins in the safety issues. Rapalog [rapamycin] therapy, alone or in combination, is becoming a cornerstone of tumor management" in neurocutaneous disorders, said Dr. David H. Viskochil, professor of pediatrics at the University of Utah, Salt Lake City, commenting on the study.

"Of course, there are emergent situations where you’ve just got to go in and get the tumor out; you can’t wait 3 months to see" if drugs work. "But if a child is just starting to show some symptoms and not deteriorating, then you can start with medicine first and see what happens," he said.

"The question is if you got [SEGAs] really early, would surgical cure be much more likely? The studies aren’t quite there yet," he said in an interview.

Ms. Yoon and Dr. Viskochil said they have no disclosures.

[email protected]

SAN DIEGO – Medical management with sirolimus or everolimus for pediatric patients with tuberous sclerosis complex and subependymal giant cell astrocytomas is more effective and safer than surgery, researchers from the University of Cincinnati and University of California, Los Angeles, have found.

Although the benign tumors have traditionally been left to surgeons, it’s become clear in recent years that rapamycin analogs are effective, too. The question has been "which [approach] is best? Medical management "is known to be pretty mild compared to the surgery," but it’s not curative, explained lead investigator Susanne Yoon, the University of Cincinnati medical student who presented the results at the annual meeting of the American Academy of Neurology.

The team compared outcomes for 23 SEGA (subependymal giant cell astrocytoma) patients who underwent surgery, 81 who took sirolimus or everolimus, and 9 who got both. The surgery patients were diagnosed when they were about 10 years old and were followed for a median of 8.9 years; the medical patients were about 7 years old when diagnosed, and were followed for a median of 2.8 years. Boys made up the majority of both groups.

None of the children who took a rapamycin analog needed surgery; tumors shrank by more than half in 61% (45). The drugs caused infections, weight change, or hyperlipidemia in some, but only 13% (11) needed to stop the drug or go to the hospital because of side effects.

Meanwhile, surgery cured just 39% (9) of the children who got it, sometimes after two or three operations; 61% (14) of those patients had prolonged hospitalizations or were hospitalized due to postoperative complications that included intracranial hemorrhage in 8, hydrocephalus/shunt malfunction in 6, neurologic impairment, and seizures.

"Not only does medical management win in efficacy, but it also wins in the safety issues. Rapalog [rapamycin] therapy, alone or in combination, is becoming a cornerstone of tumor management" in neurocutaneous disorders, said Dr. David H. Viskochil, professor of pediatrics at the University of Utah, Salt Lake City, commenting on the study.

"Of course, there are emergent situations where you’ve just got to go in and get the tumor out; you can’t wait 3 months to see" if drugs work. "But if a child is just starting to show some symptoms and not deteriorating, then you can start with medicine first and see what happens," he said.

"The question is if you got [SEGAs] really early, would surgical cure be much more likely? The studies aren’t quite there yet," he said in an interview.

Ms. Yoon and Dr. Viskochil said they have no disclosures.

[email protected]

Adults in Norway with diffuse low-grade gliomas who were treated at a hospital advocating early surgical resection had better overall survival than those treated at a hospital advocating "watchful waiting," according to a report published online Oct. 30 in JAMA.

This finding significantly strengthens the sparse evidence in support of early resection for newly diagnosed diffuse low-grade gliomas, said Dr. Asgeir S. Jakola of the department of neurosurgery, St. Olav’s University Hospital, Trondheim (Norway) and his associates.

Management of these tumors is one of the major controversies in both neurology and oncology today, largely because the effect of surgery on survival is still unclear. The only evidence available until now was based solely on uncontrolled surgical series; some of these have reported that it is safe to withhold surgery until the lesions progress, while others have reported that immediate resection improves survival and delays the time to malignant transformation.

Both patients and physicians are reluctant to undertake immediate surgery when the evidence supporting that strategy has been so tenuous. They also are concerned that the risk of early and aggressive surgery outweighs the benefit, particularly when most patients are capable of normal activity and have a reasonably long life expectancy at diagnosis, the investigators said.

It is unlikely that a randomized, controlled study comparing the two approaches will ever be performed. Dr. Jakola and his colleagues therefore conducted a retrospective, population-based parallel-cohort study at two neurosurgical centers, each of which preferred one of these strategies over the other. Their "natural experiment" was possible because in Norway, there were two such facilities that were relatively close geographically and served a homogenous population. The nationalized health care system distributes training, resources, and personnel equally throughout the country, so the two hospitals were quite similar in other respects. And patient follow-up is 100%.

The 12-year study involved 153 adults with diffuse, histologically verified supratentorial grade I and II tumors diagnosed in 1998-2009, who were followed until death or until April 2011. The median follow-up was 7 years. Gliomas included astrocytomas, oligodendrogliomas, and oligoastrocytomas.

For patients with newly diagnosed low-grade gliomas, hospital A favored biopsy and watchful waiting. The 66 patients treated there typically were followed with MRI at 3 and 6 months, then yearly thereafter. They usually were offered surgical resection, if the lesions grew or showed signs of malignant transformation.

Hospital B favored immediate maximal safe tumor resection for the 87 patients treated there, with MRI follow-up at 6 and 12 months, then annually thereafter. This strategy was not pursued in some patients, however: notably, those who were elderly or had comorbidities and were likely to die from another cause before malignant transformation would take place, and those who had very widespread tumor infiltration that made resection impractical.

The two study groups were well balanced with regard to patient age and comorbidities, and rates of surgical rescue therapy were the same. There also were no differences between the two groups in complications or acquired neurologic deficits.

At the end of the study period, 34 patients (52%) from hospital A had died, compared with only 28 patients (32%) from hospital B. Median survival was 5.9 years at hospital A, but median survival had not yet been reached at hospital B, the researchers said (JAMA 2012;308: [doi:10.1001/jama.2012.12807]).

This survival advantage increased over time. Expected 3-year survival was 70% at hospital A vs. 80% at hospital B; expected 5-year survival was 60% at hospital A vs. 74% at hospital B; and expected 7-year survival was 44% at hospital A vs. 68% at hospital B.

In a post hoc analysis that attempted to account for differences between the two study groups in prognostic factors, the survival benefit for immediate resection remained robust. It also remained robust in another post hoc analysis that examined the subgroup of patients who had the most common glioma, a grade II astrocytoma. Median survival was 5.6 years at the hospital favoring watchful waiting, compared with 9.7 years at the hospital favoring early resection, in this large subgroup of patients.

Based on these findings, hospital A has changed its preferred strategy from watchful waiting to early resection, Dr. Jakola and his associates said.

"Despite the clear survival advantage seen, clinical judgment is still necessary in individual patients with suspected low-grade glioma since results will depend on patient and disease characteristics together with surgical results in terms of resection grades and complication rates," they added.

One of Dr. Jakola’s associates reported holding stock in Sonowand, manufacturer of the 3-D ultrasound-based imaging system used in one of the study hospitals.

Adults in Norway with diffuse low-grade gliomas who were treated at a hospital advocating early surgical resection had better overall survival than those treated at a hospital advocating "watchful waiting," according to a report published online Oct. 30 in JAMA.

This finding significantly strengthens the sparse evidence in support of early resection for newly diagnosed diffuse low-grade gliomas, said Dr. Asgeir S. Jakola of the department of neurosurgery, St. Olav’s University Hospital, Trondheim (Norway) and his associates.

Management of these tumors is one of the major controversies in both neurology and oncology today, largely because the effect of surgery on survival is still unclear. The only evidence available until now was based solely on uncontrolled surgical series; some of these have reported that it is safe to withhold surgery until the lesions progress, while others have reported that immediate resection improves survival and delays the time to malignant transformation.

Both patients and physicians are reluctant to undertake immediate surgery when the evidence supporting that strategy has been so tenuous. They also are concerned that the risk of early and aggressive surgery outweighs the benefit, particularly when most patients are capable of normal activity and have a reasonably long life expectancy at diagnosis, the investigators said.

It is unlikely that a randomized, controlled study comparing the two approaches will ever be performed. Dr. Jakola and his colleagues therefore conducted a retrospective, population-based parallel-cohort study at two neurosurgical centers, each of which preferred one of these strategies over the other. Their "natural experiment" was possible because in Norway, there were two such facilities that were relatively close geographically and served a homogenous population. The nationalized health care system distributes training, resources, and personnel equally throughout the country, so the two hospitals were quite similar in other respects. And patient follow-up is 100%.

The 12-year study involved 153 adults with diffuse, histologically verified supratentorial grade I and II tumors diagnosed in 1998-2009, who were followed until death or until April 2011. The median follow-up was 7 years. Gliomas included astrocytomas, oligodendrogliomas, and oligoastrocytomas.

For patients with newly diagnosed low-grade gliomas, hospital A favored biopsy and watchful waiting. The 66 patients treated there typically were followed with MRI at 3 and 6 months, then yearly thereafter. They usually were offered surgical resection, if the lesions grew or showed signs of malignant transformation.

Hospital B favored immediate maximal safe tumor resection for the 87 patients treated there, with MRI follow-up at 6 and 12 months, then annually thereafter. This strategy was not pursued in some patients, however: notably, those who were elderly or had comorbidities and were likely to die from another cause before malignant transformation would take place, and those who had very widespread tumor infiltration that made resection impractical.

The two study groups were well balanced with regard to patient age and comorbidities, and rates of surgical rescue therapy were the same. There also were no differences between the two groups in complications or acquired neurologic deficits.

At the end of the study period, 34 patients (52%) from hospital A had died, compared with only 28 patients (32%) from hospital B. Median survival was 5.9 years at hospital A, but median survival had not yet been reached at hospital B, the researchers said (JAMA 2012;308: [doi:10.1001/jama.2012.12807]).

This survival advantage increased over time. Expected 3-year survival was 70% at hospital A vs. 80% at hospital B; expected 5-year survival was 60% at hospital A vs. 74% at hospital B; and expected 7-year survival was 44% at hospital A vs. 68% at hospital B.

In a post hoc analysis that attempted to account for differences between the two study groups in prognostic factors, the survival benefit for immediate resection remained robust. It also remained robust in another post hoc analysis that examined the subgroup of patients who had the most common glioma, a grade II astrocytoma. Median survival was 5.6 years at the hospital favoring watchful waiting, compared with 9.7 years at the hospital favoring early resection, in this large subgroup of patients.

Based on these findings, hospital A has changed its preferred strategy from watchful waiting to early resection, Dr. Jakola and his associates said.

"Despite the clear survival advantage seen, clinical judgment is still necessary in individual patients with suspected low-grade glioma since results will depend on patient and disease characteristics together with surgical results in terms of resection grades and complication rates," they added.

One of Dr. Jakola’s associates reported holding stock in Sonowand, manufacturer of the 3-D ultrasound-based imaging system used in one of the study hospitals.

Adults in Norway with diffuse low-grade gliomas who were treated at a hospital advocating early surgical resection had better overall survival than those treated at a hospital advocating "watchful waiting," according to a report published online Oct. 30 in JAMA.

This finding significantly strengthens the sparse evidence in support of early resection for newly diagnosed diffuse low-grade gliomas, said Dr. Asgeir S. Jakola of the department of neurosurgery, St. Olav’s University Hospital, Trondheim (Norway) and his associates.

Management of these tumors is one of the major controversies in both neurology and oncology today, largely because the effect of surgery on survival is still unclear. The only evidence available until now was based solely on uncontrolled surgical series; some of these have reported that it is safe to withhold surgery until the lesions progress, while others have reported that immediate resection improves survival and delays the time to malignant transformation.

Both patients and physicians are reluctant to undertake immediate surgery when the evidence supporting that strategy has been so tenuous. They also are concerned that the risk of early and aggressive surgery outweighs the benefit, particularly when most patients are capable of normal activity and have a reasonably long life expectancy at diagnosis, the investigators said.

It is unlikely that a randomized, controlled study comparing the two approaches will ever be performed. Dr. Jakola and his colleagues therefore conducted a retrospective, population-based parallel-cohort study at two neurosurgical centers, each of which preferred one of these strategies over the other. Their "natural experiment" was possible because in Norway, there were two such facilities that were relatively close geographically and served a homogenous population. The nationalized health care system distributes training, resources, and personnel equally throughout the country, so the two hospitals were quite similar in other respects. And patient follow-up is 100%.

The 12-year study involved 153 adults with diffuse, histologically verified supratentorial grade I and II tumors diagnosed in 1998-2009, who were followed until death or until April 2011. The median follow-up was 7 years. Gliomas included astrocytomas, oligodendrogliomas, and oligoastrocytomas.

For patients with newly diagnosed low-grade gliomas, hospital A favored biopsy and watchful waiting. The 66 patients treated there typically were followed with MRI at 3 and 6 months, then yearly thereafter. They usually were offered surgical resection, if the lesions grew or showed signs of malignant transformation.

Hospital B favored immediate maximal safe tumor resection for the 87 patients treated there, with MRI follow-up at 6 and 12 months, then annually thereafter. This strategy was not pursued in some patients, however: notably, those who were elderly or had comorbidities and were likely to die from another cause before malignant transformation would take place, and those who had very widespread tumor infiltration that made resection impractical.

The two study groups were well balanced with regard to patient age and comorbidities, and rates of surgical rescue therapy were the same. There also were no differences between the two groups in complications or acquired neurologic deficits.

At the end of the study period, 34 patients (52%) from hospital A had died, compared with only 28 patients (32%) from hospital B. Median survival was 5.9 years at hospital A, but median survival had not yet been reached at hospital B, the researchers said (JAMA 2012;308: [doi:10.1001/jama.2012.12807]).

This survival advantage increased over time. Expected 3-year survival was 70% at hospital A vs. 80% at hospital B; expected 5-year survival was 60% at hospital A vs. 74% at hospital B; and expected 7-year survival was 44% at hospital A vs. 68% at hospital B.

In a post hoc analysis that attempted to account for differences between the two study groups in prognostic factors, the survival benefit for immediate resection remained robust. It also remained robust in another post hoc analysis that examined the subgroup of patients who had the most common glioma, a grade II astrocytoma. Median survival was 5.6 years at the hospital favoring watchful waiting, compared with 9.7 years at the hospital favoring early resection, in this large subgroup of patients.

Based on these findings, hospital A has changed its preferred strategy from watchful waiting to early resection, Dr. Jakola and his associates said.

"Despite the clear survival advantage seen, clinical judgment is still necessary in individual patients with suspected low-grade glioma since results will depend on patient and disease characteristics together with surgical results in terms of resection grades and complication rates," they added.

One of Dr. Jakola’s associates reported holding stock in Sonowand, manufacturer of the 3-D ultrasound-based imaging system used in one of the study hospitals.

BOSTON – Memantine, a drug normally prescribed for slowing cognitive decline in Alzheimer’s disease, can help to preserve cognitive function in cancer patients who have undergone whole brain irradiation, a study showed.

In a phase III trial, patients with brain metastases were randomly assigned to take 20 mg memantine (Namenda) or placebo daily for 24 weeks after whole brain radiation therapy (WBRT). The memantine cohort had a 17% relative reduction in cognitive decline compared with patients who got a placebo, Dr. Nadia N. Laack reported at the annual meeting of the American Society for Radiation Oncology.

Courtesy of ASTRO

The finding teetered on the edge of statistical significance (P = .059), however, because only one-third of patients (32%) completed the 24 weeks of drug therapy, due to death (survival was poorer than expected), disease progression, or noncompliance, said Dr. Laack. a radiation oncologist at the Mayo Clinic in Rochester, Minn.

"Overall, we feel that the weight of evidence supports our conclusion that memantine helps to preserve cognitive function after whole brain radiotherapy in patients with brain metastases," Dr. Laack said at a briefing prior to presenting the data at a plenary session.

WBRT is associated with cognitive impairment in a majority of patients who receive it, Dr. Laack said, noting that at 4 months post radiation, 60% of patients will have declines in one or more cognitive domains.

Because the mechanism of decline is similar to that seen with Alzheimer\'s and vascular dementias, and because memantine has been shown to modestly improve mild to moderate cognition in both dementia types, Dr. Laack and his colleagues hypothesized that it might protect brains exposed to therapeutic doses of radiation.

A total of 508 patients were tested at baseline and at 8, 16, 24, and 52 weeks after radiation with 37.5 Gy in 15 fractions. They were evaluated with MRI and cognitive assessment; domains of memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life were evaluated. Median overall follow-up was 12.4 months.

There were no differences between the treatment groups in overall survival at a median of 6 months or in progression-free survival at 5 months.

Among 149 patients available for analysis at 24 weeks, patients who took memantine had a significantly longer time to memory decline than did those on placebo (P = .02), and had a trend toward less decline in the primary end point, the Hopkins Verbal Learning Test–Revised delayed recall instrument (median decline of 0 standard deviation, vs. –2 standard deviations for patients on placebo).

For the secondary objective of cognitive function decline/failure, defined as a change greater than reversible cognitive impairment or 2 standard deviations decline from baseline on any domain of brain function, the hazard ratio for memantine at 24 weeks was 0.784 (P = .01), indicating a significant reduction in the incidence of cognitive dysfunction.

"Although memantine was discontinued at 6 months, the effect on cognitive function was maintained for the duration of the trial, suggesting that memantine may be preventing radiation injury rather than simply treating cognitive dysfunction," Dr. Laack said.

The trial was sponsored by grants from the National Cancer Institute and Forest Pharmaceuticals. Dr. Laack reported no relevant financial disclosures.

BOSTON – Memantine, a drug normally prescribed for slowing cognitive decline in Alzheimer’s disease, can help to preserve cognitive function in cancer patients who have undergone whole brain irradiation, a study showed.

In a phase III trial, patients with brain metastases were randomly assigned to take 20 mg memantine (Namenda) or placebo daily for 24 weeks after whole brain radiation therapy (WBRT). The memantine cohort had a 17% relative reduction in cognitive decline compared with patients who got a placebo, Dr. Nadia N. Laack reported at the annual meeting of the American Society for Radiation Oncology.

Courtesy of ASTRO

The finding teetered on the edge of statistical significance (P = .059), however, because only one-third of patients (32%) completed the 24 weeks of drug therapy, due to death (survival was poorer than expected), disease progression, or noncompliance, said Dr. Laack. a radiation oncologist at the Mayo Clinic in Rochester, Minn.

"Overall, we feel that the weight of evidence supports our conclusion that memantine helps to preserve cognitive function after whole brain radiotherapy in patients with brain metastases," Dr. Laack said at a briefing prior to presenting the data at a plenary session.

WBRT is associated with cognitive impairment in a majority of patients who receive it, Dr. Laack said, noting that at 4 months post radiation, 60% of patients will have declines in one or more cognitive domains.

Because the mechanism of decline is similar to that seen with Alzheimer\'s and vascular dementias, and because memantine has been shown to modestly improve mild to moderate cognition in both dementia types, Dr. Laack and his colleagues hypothesized that it might protect brains exposed to therapeutic doses of radiation.

A total of 508 patients were tested at baseline and at 8, 16, 24, and 52 weeks after radiation with 37.5 Gy in 15 fractions. They were evaluated with MRI and cognitive assessment; domains of memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life were evaluated. Median overall follow-up was 12.4 months.

There were no differences between the treatment groups in overall survival at a median of 6 months or in progression-free survival at 5 months.

Among 149 patients available for analysis at 24 weeks, patients who took memantine had a significantly longer time to memory decline than did those on placebo (P = .02), and had a trend toward less decline in the primary end point, the Hopkins Verbal Learning Test–Revised delayed recall instrument (median decline of 0 standard deviation, vs. –2 standard deviations for patients on placebo).

For the secondary objective of cognitive function decline/failure, defined as a change greater than reversible cognitive impairment or 2 standard deviations decline from baseline on any domain of brain function, the hazard ratio for memantine at 24 weeks was 0.784 (P = .01), indicating a significant reduction in the incidence of cognitive dysfunction.

"Although memantine was discontinued at 6 months, the effect on cognitive function was maintained for the duration of the trial, suggesting that memantine may be preventing radiation injury rather than simply treating cognitive dysfunction," Dr. Laack said.

The trial was sponsored by grants from the National Cancer Institute and Forest Pharmaceuticals. Dr. Laack reported no relevant financial disclosures.

BOSTON – Memantine, a drug normally prescribed for slowing cognitive decline in Alzheimer’s disease, can help to preserve cognitive function in cancer patients who have undergone whole brain irradiation, a study showed.

In a phase III trial, patients with brain metastases were randomly assigned to take 20 mg memantine (Namenda) or placebo daily for 24 weeks after whole brain radiation therapy (WBRT). The memantine cohort had a 17% relative reduction in cognitive decline compared with patients who got a placebo, Dr. Nadia N. Laack reported at the annual meeting of the American Society for Radiation Oncology.

Courtesy of ASTRO

The finding teetered on the edge of statistical significance (P = .059), however, because only one-third of patients (32%) completed the 24 weeks of drug therapy, due to death (survival was poorer than expected), disease progression, or noncompliance, said Dr. Laack. a radiation oncologist at the Mayo Clinic in Rochester, Minn.

"Overall, we feel that the weight of evidence supports our conclusion that memantine helps to preserve cognitive function after whole brain radiotherapy in patients with brain metastases," Dr. Laack said at a briefing prior to presenting the data at a plenary session.

WBRT is associated with cognitive impairment in a majority of patients who receive it, Dr. Laack said, noting that at 4 months post radiation, 60% of patients will have declines in one or more cognitive domains.

Because the mechanism of decline is similar to that seen with Alzheimer\'s and vascular dementias, and because memantine has been shown to modestly improve mild to moderate cognition in both dementia types, Dr. Laack and his colleagues hypothesized that it might protect brains exposed to therapeutic doses of radiation.

A total of 508 patients were tested at baseline and at 8, 16, 24, and 52 weeks after radiation with 37.5 Gy in 15 fractions. They were evaluated with MRI and cognitive assessment; domains of memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life were evaluated. Median overall follow-up was 12.4 months.

There were no differences between the treatment groups in overall survival at a median of 6 months or in progression-free survival at 5 months.

Among 149 patients available for analysis at 24 weeks, patients who took memantine had a significantly longer time to memory decline than did those on placebo (P = .02), and had a trend toward less decline in the primary end point, the Hopkins Verbal Learning Test–Revised delayed recall instrument (median decline of 0 standard deviation, vs. –2 standard deviations for patients on placebo).

For the secondary objective of cognitive function decline/failure, defined as a change greater than reversible cognitive impairment or 2 standard deviations decline from baseline on any domain of brain function, the hazard ratio for memantine at 24 weeks was 0.784 (P = .01), indicating a significant reduction in the incidence of cognitive dysfunction.

"Although memantine was discontinued at 6 months, the effect on cognitive function was maintained for the duration of the trial, suggesting that memantine may be preventing radiation injury rather than simply treating cognitive dysfunction," Dr. Laack said.

The trial was sponsored by grants from the National Cancer Institute and Forest Pharmaceuticals. Dr. Laack reported no relevant financial disclosures.

Objectives: This phase III trial asks whether the addition of temozolomide (Temodar) to radiation therapy can improve progression-free survival and/or overall survival of patients with grade 2 glioma at the most recent pathological diagnosis.

Key entry or exclusion criteria: Patients with a previous pathological diagnosis of grade 3 or 4 are excluded, as are patients with prior radiotherapy, cytotoxic chemotherapy, radiosurgery, or investigational therapy for the brain tumor. Prior surgery is permitted.

Locations: 173 sites

Goal: 540 patients

Study sponsor: Eastern Cooperative Oncology Group in collaboration with the National Cancer Institute.

Link for more information: clinicaltrials.gov/ct2/show/study/NCT00978458

NIH clinical trials identifier: NCT00978458

Objectives: This phase III trial asks whether the addition of temozolomide (Temodar) to radiation therapy can improve progression-free survival and/or overall survival of patients with grade 2 glioma at the most recent pathological diagnosis.

Key entry or exclusion criteria: Patients with a previous pathological diagnosis of grade 3 or 4 are excluded, as are patients with prior radiotherapy, cytotoxic chemotherapy, radiosurgery, or investigational therapy for the brain tumor. Prior surgery is permitted.

Locations: 173 sites

Goal: 540 patients

Study sponsor: Eastern Cooperative Oncology Group in collaboration with the National Cancer Institute.

Link for more information: clinicaltrials.gov/ct2/show/study/NCT00978458

NIH clinical trials identifier: NCT00978458

Objectives: This phase III trial asks whether the addition of temozolomide (Temodar) to radiation therapy can improve progression-free survival and/or overall survival of patients with grade 2 glioma at the most recent pathological diagnosis.

Key entry or exclusion criteria: Patients with a previous pathological diagnosis of grade 3 or 4 are excluded, as are patients with prior radiotherapy, cytotoxic chemotherapy, radiosurgery, or investigational therapy for the brain tumor. Prior surgery is permitted.

Locations: 173 sites

Goal: 540 patients

Study sponsor: Eastern Cooperative Oncology Group in collaboration with the National Cancer Institute.

Link for more information: clinicaltrials.gov/ct2/show/study/NCT00978458

NIH clinical trials identifier: NCT00978458

VIENNA – Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.

Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.

Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.

Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.

‘No Conclusion Can Be Made...’

In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).

The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.

Sara Freeman/IMNG Medical Media

"No conclusion should be made from these results," said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.

Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.

Trial Excluded Asymptomatic Brain Metastases

"The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population," Dr. Stephen Johnston, who was not involved the study, commented in an interview.

"The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point," added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.

CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.

In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m²/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m²/day on days 1-14 every 21 days).

PFS Longer with Trastuzumab and Capecitabine

The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).

This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.

While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.

Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.

Nevertheless, "I think the question about the effects of lapatinib on brain metastases is still relevant," he said.

"We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer," Dr. Johnston explained. "This is where lapatinib may still have a role."

LANDSCAPE Results Favorable

The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.

Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).

Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.

"This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity," Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.

The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.

Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.

VIENNA – Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.

Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.

Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.

Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.

‘No Conclusion Can Be Made...’

In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).

The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.

Sara Freeman/IMNG Medical Media

"No conclusion should be made from these results," said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.

Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.

Trial Excluded Asymptomatic Brain Metastases

"The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population," Dr. Stephen Johnston, who was not involved the study, commented in an interview.

"The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point," added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.

CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.

In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m²/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m²/day on days 1-14 every 21 days).

PFS Longer with Trastuzumab and Capecitabine

The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).

This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.

While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.

Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.

Nevertheless, "I think the question about the effects of lapatinib on brain metastases is still relevant," he said.

"We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer," Dr. Johnston explained. "This is where lapatinib may still have a role."

LANDSCAPE Results Favorable

The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.

Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).

Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.

"This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity," Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.

The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.

Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.

VIENNA – Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.

Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.

Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.

Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.

‘No Conclusion Can Be Made...’

In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).

The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.

Sara Freeman/IMNG Medical Media

"No conclusion should be made from these results," said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.

Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.

Trial Excluded Asymptomatic Brain Metastases

"The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population," Dr. Stephen Johnston, who was not involved the study, commented in an interview.

"The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point," added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.

CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.

In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m²/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m²/day on days 1-14 every 21 days).

PFS Longer with Trastuzumab and Capecitabine

The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).

This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.

While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.

Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.

Nevertheless, "I think the question about the effects of lapatinib on brain metastases is still relevant," he said.

"We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer," Dr. Johnston explained. "This is where lapatinib may still have a role."

LANDSCAPE Results Favorable

The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.

Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).

Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.

"This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity," Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.

The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.

Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.