A PET imaging protocol using an amino acid analog radiotracer in patients with recurrent high-grade gliomas identified responses to treatment with bevacizumab as early as 2 weeks after starting therapy in a prospective study.

In the 28-patient pilot study, the metabolic tumor volume measured in follow-up PET scans with 6-¹⁸F-fluoro-L-DOPA (¹⁸F-FDOPA) at 2 and 6 weeks after the baseline scan proved to be the most significant predictor of survival with the method.

There is currently no reliable way to predict treatment response noninvasively in patients with malignant glioma, which has only 6% overall survival at 5 years. Chemotherapeutics have toxic side effects and are expensive, "so from the patient’s point of view, if a treatment doesn’t work, it’s important to get that information as early as possible," said the senior investigator of the study, Dr. Wei Chen of the division of molecular and medical pharmacology at the University of California, Los Angeles.

The ability to detect treatment response only 2 weeks after the start of treatment is the shortest interval yet reported, Dr. Chen said. In a study published last year, she and her colleagues reported that another PET radiotracer, 3´-deoxy-3´-[¹⁸F]-fluorothymidine (¹⁸F-FLT), could be used to monitor the response of recurrent high-grade gliomas to treatment (J. Nucl. Med. 2012;53:29-36). However, change in response to treatment with bevacizumab (Avastin) could not be detected with ¹⁸F-FLT until 6 weeks after starting therapy in that study, compared with 2 weeks for ¹⁸F-FDOPA in the current study.

The ¹⁸F-FDOPA technique of assessing metabolic tumor volume as early as 2 weeks after starting bevacizumab proved to be a significant predictor of overall and progression-free survival. The 17 metabolic responders survived a median of 12.1 months, compared with 3.5 months for 11 nonresponders. In comparison, when MRI was used to determine response, the survival difference shrank (12.9 months vs. 9.0 months). All patients in the study eventually died.

The investigators chose to use bevacizumab because "it is the most effective treatment," with a significant treatment response of 50% instead of 5%-10% with other drugs, Dr. Chen said in an interview. "But in terms of monitoring, it doesn’t matter which agent is used for treatment."

¹⁸F-FDOPA is normally used to assess the striatal dopaminergic system in patients with movement disorders. But it works in assessing tumor treatment response because the higher metabolic rate of cancer cells causes greater uptake of the tracer through a phenylalanine and tyrosine transporter. Conventional MRI assessments for tumor recurrence cannot distinguish tumor from scar tissue left by surgery or radiation, and cannot determine the amount of change until 1.5 to 3 months, according to Dr. Chen.

In eight of nine discrepant cases between PET and MRI, ¹⁸F-FDOPA PET demonstrated treatment response earlier than MRI.

The study was supported by grants from the National Cancer Institute and the Department of Energy. Dr. Chen had no relevant disclosures.

A PET imaging protocol using an amino acid analog radiotracer in patients with recurrent high-grade gliomas identified responses to treatment with bevacizumab as early as 2 weeks after starting therapy in a prospective study.

In the 28-patient pilot study, the metabolic tumor volume measured in follow-up PET scans with 6-¹⁸F-fluoro-L-DOPA (¹⁸F-FDOPA) at 2 and 6 weeks after the baseline scan proved to be the most significant predictor of survival with the method.

There is currently no reliable way to predict treatment response noninvasively in patients with malignant glioma, which has only 6% overall survival at 5 years. Chemotherapeutics have toxic side effects and are expensive, "so from the patient’s point of view, if a treatment doesn’t work, it’s important to get that information as early as possible," said the senior investigator of the study, Dr. Wei Chen of the division of molecular and medical pharmacology at the University of California, Los Angeles.

The ability to detect treatment response only 2 weeks after the start of treatment is the shortest interval yet reported, Dr. Chen said. In a study published last year, she and her colleagues reported that another PET radiotracer, 3´-deoxy-3´-[¹⁸F]-fluorothymidine (¹⁸F-FLT), could be used to monitor the response of recurrent high-grade gliomas to treatment (J. Nucl. Med. 2012;53:29-36). However, change in response to treatment with bevacizumab (Avastin) could not be detected with ¹⁸F-FLT until 6 weeks after starting therapy in that study, compared with 2 weeks for ¹⁸F-FDOPA in the current study.

The ¹⁸F-FDOPA technique of assessing metabolic tumor volume as early as 2 weeks after starting bevacizumab proved to be a significant predictor of overall and progression-free survival. The 17 metabolic responders survived a median of 12.1 months, compared with 3.5 months for 11 nonresponders. In comparison, when MRI was used to determine response, the survival difference shrank (12.9 months vs. 9.0 months). All patients in the study eventually died.

The investigators chose to use bevacizumab because "it is the most effective treatment," with a significant treatment response of 50% instead of 5%-10% with other drugs, Dr. Chen said in an interview. "But in terms of monitoring, it doesn’t matter which agent is used for treatment."

¹⁸F-FDOPA is normally used to assess the striatal dopaminergic system in patients with movement disorders. But it works in assessing tumor treatment response because the higher metabolic rate of cancer cells causes greater uptake of the tracer through a phenylalanine and tyrosine transporter. Conventional MRI assessments for tumor recurrence cannot distinguish tumor from scar tissue left by surgery or radiation, and cannot determine the amount of change until 1.5 to 3 months, according to Dr. Chen.

In eight of nine discrepant cases between PET and MRI, ¹⁸F-FDOPA PET demonstrated treatment response earlier than MRI.

The study was supported by grants from the National Cancer Institute and the Department of Energy. Dr. Chen had no relevant disclosures.

A PET imaging protocol using an amino acid analog radiotracer in patients with recurrent high-grade gliomas identified responses to treatment with bevacizumab as early as 2 weeks after starting therapy in a prospective study.

In the 28-patient pilot study, the metabolic tumor volume measured in follow-up PET scans with 6-¹⁸F-fluoro-L-DOPA (¹⁸F-FDOPA) at 2 and 6 weeks after the baseline scan proved to be the most significant predictor of survival with the method.

There is currently no reliable way to predict treatment response noninvasively in patients with malignant glioma, which has only 6% overall survival at 5 years. Chemotherapeutics have toxic side effects and are expensive, "so from the patient’s point of view, if a treatment doesn’t work, it’s important to get that information as early as possible," said the senior investigator of the study, Dr. Wei Chen of the division of molecular and medical pharmacology at the University of California, Los Angeles.

The ability to detect treatment response only 2 weeks after the start of treatment is the shortest interval yet reported, Dr. Chen said. In a study published last year, she and her colleagues reported that another PET radiotracer, 3´-deoxy-3´-[¹⁸F]-fluorothymidine (¹⁸F-FLT), could be used to monitor the response of recurrent high-grade gliomas to treatment (J. Nucl. Med. 2012;53:29-36). However, change in response to treatment with bevacizumab (Avastin) could not be detected with ¹⁸F-FLT until 6 weeks after starting therapy in that study, compared with 2 weeks for ¹⁸F-FDOPA in the current study.

The ¹⁸F-FDOPA technique of assessing metabolic tumor volume as early as 2 weeks after starting bevacizumab proved to be a significant predictor of overall and progression-free survival. The 17 metabolic responders survived a median of 12.1 months, compared with 3.5 months for 11 nonresponders. In comparison, when MRI was used to determine response, the survival difference shrank (12.9 months vs. 9.0 months). All patients in the study eventually died.

The investigators chose to use bevacizumab because "it is the most effective treatment," with a significant treatment response of 50% instead of 5%-10% with other drugs, Dr. Chen said in an interview. "But in terms of monitoring, it doesn’t matter which agent is used for treatment."

¹⁸F-FDOPA is normally used to assess the striatal dopaminergic system in patients with movement disorders. But it works in assessing tumor treatment response because the higher metabolic rate of cancer cells causes greater uptake of the tracer through a phenylalanine and tyrosine transporter. Conventional MRI assessments for tumor recurrence cannot distinguish tumor from scar tissue left by surgery or radiation, and cannot determine the amount of change until 1.5 to 3 months, according to Dr. Chen.

In eight of nine discrepant cases between PET and MRI, ¹⁸F-FDOPA PET demonstrated treatment response earlier than MRI.

The study was supported by grants from the National Cancer Institute and the Department of Energy. Dr. Chen had no relevant disclosures.

CHICAGO – Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*

The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.

Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).

Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.

"This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors," Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A survival advantage with combination therapy was also seen in patients with MGMT (O⁶-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.

The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.

Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.

He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.

"The thing that’s important is that we now know that we get this huge increase in survival with PCV," he said. "The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions."

Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.

He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.

"If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?" he asked.

EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m² on day 1, procarbazine 60 mg/m² on day 8-21 and IV vincristine 1.4 mg/m² on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.

In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).

In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).

Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).

In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.

Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.

In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).

Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).

In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).

The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).

The same phenomenon was reported in the EORTC cohort.

"It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in," Dr. van den Bent speculated. "We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years."

Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.

Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.

Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.

RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.

* This story has been updated and revised on 6/8/2012.

CHICAGO – Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*

The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.

Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).

Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.

"This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors," Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A survival advantage with combination therapy was also seen in patients with MGMT (O⁶-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.

The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.

Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.

He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.

"The thing that’s important is that we now know that we get this huge increase in survival with PCV," he said. "The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions."

Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.

He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.

"If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?" he asked.

EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m² on day 1, procarbazine 60 mg/m² on day 8-21 and IV vincristine 1.4 mg/m² on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.

In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).

In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).

Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).

In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.

Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.

In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).

Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).

In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).

The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).

The same phenomenon was reported in the EORTC cohort.

"It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in," Dr. van den Bent speculated. "We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years."

Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.

Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.

Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.

RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.

* This story has been updated and revised on 6/8/2012.

CHICAGO – Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*

The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.

Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).

Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.

"This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors," Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A survival advantage with combination therapy was also seen in patients with MGMT (O⁶-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.

The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.

Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.

He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.

"The thing that’s important is that we now know that we get this huge increase in survival with PCV," he said. "The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions."

Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.

He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.

"If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?" he asked.

EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m² on day 1, procarbazine 60 mg/m² on day 8-21 and IV vincristine 1.4 mg/m² on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.

In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).

In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).

Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).

In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.

Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.

In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).

Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).

In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).

The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).

The same phenomenon was reported in the EORTC cohort.

"It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in," Dr. van den Bent speculated. "We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years."

Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.

Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.

Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.

RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.

* This story has been updated and revised on 6/8/2012.

The Toxicity of Chemotherapy and Radiotherapy on the Central Nervous System

• Ivo W. Tremont-Lukats, MD

  

• Available online 26 April 2012.

• http://dx.doi.org/10.1016/j.suponc.2012.04.001,

• Permissions & Reprints

Central neurotoxicity of chemotherapy and radiotherapy is so frequent that every clinician should recognize and treat this complication, preferably with a neurologist experienced in these cases. Unfortunately, in most neurology and oncology training programs in the United States, there is very little exposure to the central neurotoxicity of anticancer drugs and other modalities. Yet, the importance of the topic is high and will always be.

One of the main forces driving the knowledge behind this area began at the Memorial Sloan-Kettering Cancer Center with Posner ^{[1] and [2]} and in Europe with Hildebrand. ^[3] Others have understood that the effective management of CNS toxicity is as important as the treatment of brain tumors in neuro-oncology and are now making efforts in spreading the message: we must learn to recognize, treat, or prevent the neurotoxicity of anticancer therapies. In the past 10 years, there have been reviews on neurological complications; ^{[4] and [5]} and yet there is still little interest, and research is a low priority.

In this issue of The Journal of Supportive Oncology, Rinne and collaborators present a welcome update on this often neglected aspect of neuro-oncology. They present a complex problem in an easy flow of ideas, beginning with the neurotoxicity of radiotherapy, then including the contribution of chemotherapy and novel therapies targeted to CNS morbidity. This review is thorough, up to date, and one of the few published by a nonneurological journal. Enjoy.¹

The Toxicity of Chemotherapy and Radiotherapy on the Central Nervous System

• Ivo W. Tremont-Lukats, MD

  

• Available online 26 April 2012.

• http://dx.doi.org/10.1016/j.suponc.2012.04.001,

• Permissions & Reprints

Central neurotoxicity of chemotherapy and radiotherapy is so frequent that every clinician should recognize and treat this complication, preferably with a neurologist experienced in these cases. Unfortunately, in most neurology and oncology training programs in the United States, there is very little exposure to the central neurotoxicity of anticancer drugs and other modalities. Yet, the importance of the topic is high and will always be.

One of the main forces driving the knowledge behind this area began at the Memorial Sloan-Kettering Cancer Center with Posner ^{[1] and [2]} and in Europe with Hildebrand. ^[3] Others have understood that the effective management of CNS toxicity is as important as the treatment of brain tumors in neuro-oncology and are now making efforts in spreading the message: we must learn to recognize, treat, or prevent the neurotoxicity of anticancer therapies. In the past 10 years, there have been reviews on neurological complications; ^{[4] and [5]} and yet there is still little interest, and research is a low priority.

In this issue of The Journal of Supportive Oncology, Rinne and collaborators present a welcome update on this often neglected aspect of neuro-oncology. They present a complex problem in an easy flow of ideas, beginning with the neurotoxicity of radiotherapy, then including the contribution of chemotherapy and novel therapies targeted to CNS morbidity. This review is thorough, up to date, and one of the few published by a nonneurological journal. Enjoy.¹

The Toxicity of Chemotherapy and Radiotherapy on the Central Nervous System

• Ivo W. Tremont-Lukats, MD

  

• Available online 26 April 2012.

• http://dx.doi.org/10.1016/j.suponc.2012.04.001,

• Permissions & Reprints

Central neurotoxicity of chemotherapy and radiotherapy is so frequent that every clinician should recognize and treat this complication, preferably with a neurologist experienced in these cases. Unfortunately, in most neurology and oncology training programs in the United States, there is very little exposure to the central neurotoxicity of anticancer drugs and other modalities. Yet, the importance of the topic is high and will always be.

One of the main forces driving the knowledge behind this area began at the Memorial Sloan-Kettering Cancer Center with Posner ^{[1] and [2]} and in Europe with Hildebrand. ^[3] Others have understood that the effective management of CNS toxicity is as important as the treatment of brain tumors in neuro-oncology and are now making efforts in spreading the message: we must learn to recognize, treat, or prevent the neurotoxicity of anticancer therapies. In the past 10 years, there have been reviews on neurological complications; ^{[4] and [5]} and yet there is still little interest, and research is a low priority.

In this issue of The Journal of Supportive Oncology, Rinne and collaborators present a welcome update on this often neglected aspect of neuro-oncology. They present a complex problem in an easy flow of ideas, beginning with the neurotoxicity of radiotherapy, then including the contribution of chemotherapy and novel therapies targeted to CNS morbidity. This review is thorough, up to date, and one of the few published by a nonneurological journal. Enjoy.¹

CHICAGO – Immunotherapy with peptide vaccines may offer a much-needed therapeutic option for gliomas in children, which carry a poor prognosis despite current treatments.

In a pilot trial of subcutaneous vaccinations with peptides for glioma-associated antigen (GAA) epitopes in children who have been newly diagnosed with brain stem gliomas, cerebral high-grade gliomas, or recurrent gliomas, the immunotherapy was well tolerated and demonstrated immunologic and clinical activity, Dr. Ian F. Pollack reported April 2 at the annual meeting of the American Association for Cancer Research.

© Todd Buchanan/2012 AACR

Based on significant experience with immunotherapy for adult gliomas, "we extended these insights to childhood gliomas – malignant astrocytomas of the brain stem and cerebral hemispheres and recurrent low-grade gliomas – based on our observations of their glioma-associated antigen expression profiles," Dr. Pollack explained during a press conference.

For the pilot study, Dr. Pollack, chief of pediatric neurosurgery at Children’s Hospital of Pittsburgh Brain Care Institute, and his colleagues have enrolled 27 human leukocyte antigen (HLA) A2–positive children to date, including 16 who are newly diagnosed with brain stem gliomas, 5 with newly diagnosed high-grade gliomas, and 6 with recurrent gliomas. The GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13RA2), and survivin, he said.

All of the children received eight courses of subcutaneous vaccinations with peptides for GAA epitopes emulsified in Montanide-ISA-51 every 3 weeks, along with intramuscular injections of the immunoadjuvant poly-ICLC, which promotes the infiltration of effector T cells into intracranial gliomas.

"Our primary end points were safety and T-cell response against vaccine-targeted [GAAs]," he said, noting that treatment response was assessed clinically and by MRI.

The preliminary results reported at the meeting are based on an interim analysis of 22 evaluable patients. To date, no non–central nervous system toxicities have limited the vaccine dosages, Dr. Pollack said. Of the 22 children, 4 showed signs of rapidly progressive disease, 14 had stable disease for more than 3 months, 3 had sustained partial responses, and 1 had prolonged disease-free status after surgery, he reported.

Symptomatic "pseudoprogression" – consisting of transient neurologic deterioration and tumor enlargement, followed by tumor regression and stabilization on decreasing steroid doses with sustained partial response – was observed in four of the children with brain stem glioma, said Dr. Pollack, who is also codirector of the University of Pittsburgh Cancer Institute’s brain tumor program.

Results of the ELISPOT (enzyme-linked immunosorbent spot) assay, which was completed in seven of the children, showed responses in six of them. Specifically, the investigators observed responses to IL-13RA2 in five cases, EphA2 in three cases, and survivin in three cases, Dr. Pollack said.

"Based on what we’ve seen so far, it seems that these kids are able to mount immune responses to the vaccine at high rates, possibly higher than we’ve seen in adult studies," likely because of their robust immune systems, he said in an interview.

The observation of immunologic and clinical response – particularly the evidence of tumor shrinkage in children with very high-risk tumors – "has been extremely encouraging and somewhat surprising," Dr. Pollack reported. "This is the first study of its type that examined peptide vaccine therapy for children with brain tumors like this."

The findings are especially notable because children with these tumors generally do not respond well to standard chemotherapy, he said, stressing that if further study validates the early findings, "immunotherapy may be a promising strategy to control tumor growth."

The study was funded by the National Institutes of Health. Dr. Pollack disclosed having no potential conflicts of interest.

CHICAGO – Immunotherapy with peptide vaccines may offer a much-needed therapeutic option for gliomas in children, which carry a poor prognosis despite current treatments.

In a pilot trial of subcutaneous vaccinations with peptides for glioma-associated antigen (GAA) epitopes in children who have been newly diagnosed with brain stem gliomas, cerebral high-grade gliomas, or recurrent gliomas, the immunotherapy was well tolerated and demonstrated immunologic and clinical activity, Dr. Ian F. Pollack reported April 2 at the annual meeting of the American Association for Cancer Research.

© Todd Buchanan/2012 AACR

Based on significant experience with immunotherapy for adult gliomas, "we extended these insights to childhood gliomas – malignant astrocytomas of the brain stem and cerebral hemispheres and recurrent low-grade gliomas – based on our observations of their glioma-associated antigen expression profiles," Dr. Pollack explained during a press conference.

For the pilot study, Dr. Pollack, chief of pediatric neurosurgery at Children’s Hospital of Pittsburgh Brain Care Institute, and his colleagues have enrolled 27 human leukocyte antigen (HLA) A2–positive children to date, including 16 who are newly diagnosed with brain stem gliomas, 5 with newly diagnosed high-grade gliomas, and 6 with recurrent gliomas. The GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13RA2), and survivin, he said.

All of the children received eight courses of subcutaneous vaccinations with peptides for GAA epitopes emulsified in Montanide-ISA-51 every 3 weeks, along with intramuscular injections of the immunoadjuvant poly-ICLC, which promotes the infiltration of effector T cells into intracranial gliomas.

"Our primary end points were safety and T-cell response against vaccine-targeted [GAAs]," he said, noting that treatment response was assessed clinically and by MRI.

The preliminary results reported at the meeting are based on an interim analysis of 22 evaluable patients. To date, no non–central nervous system toxicities have limited the vaccine dosages, Dr. Pollack said. Of the 22 children, 4 showed signs of rapidly progressive disease, 14 had stable disease for more than 3 months, 3 had sustained partial responses, and 1 had prolonged disease-free status after surgery, he reported.

Symptomatic "pseudoprogression" – consisting of transient neurologic deterioration and tumor enlargement, followed by tumor regression and stabilization on decreasing steroid doses with sustained partial response – was observed in four of the children with brain stem glioma, said Dr. Pollack, who is also codirector of the University of Pittsburgh Cancer Institute’s brain tumor program.

Results of the ELISPOT (enzyme-linked immunosorbent spot) assay, which was completed in seven of the children, showed responses in six of them. Specifically, the investigators observed responses to IL-13RA2 in five cases, EphA2 in three cases, and survivin in three cases, Dr. Pollack said.

"Based on what we’ve seen so far, it seems that these kids are able to mount immune responses to the vaccine at high rates, possibly higher than we’ve seen in adult studies," likely because of their robust immune systems, he said in an interview.

The observation of immunologic and clinical response – particularly the evidence of tumor shrinkage in children with very high-risk tumors – "has been extremely encouraging and somewhat surprising," Dr. Pollack reported. "This is the first study of its type that examined peptide vaccine therapy for children with brain tumors like this."

The findings are especially notable because children with these tumors generally do not respond well to standard chemotherapy, he said, stressing that if further study validates the early findings, "immunotherapy may be a promising strategy to control tumor growth."

The study was funded by the National Institutes of Health. Dr. Pollack disclosed having no potential conflicts of interest.

CHICAGO – Immunotherapy with peptide vaccines may offer a much-needed therapeutic option for gliomas in children, which carry a poor prognosis despite current treatments.

In a pilot trial of subcutaneous vaccinations with peptides for glioma-associated antigen (GAA) epitopes in children who have been newly diagnosed with brain stem gliomas, cerebral high-grade gliomas, or recurrent gliomas, the immunotherapy was well tolerated and demonstrated immunologic and clinical activity, Dr. Ian F. Pollack reported April 2 at the annual meeting of the American Association for Cancer Research.

© Todd Buchanan/2012 AACR

Based on significant experience with immunotherapy for adult gliomas, "we extended these insights to childhood gliomas – malignant astrocytomas of the brain stem and cerebral hemispheres and recurrent low-grade gliomas – based on our observations of their glioma-associated antigen expression profiles," Dr. Pollack explained during a press conference.

For the pilot study, Dr. Pollack, chief of pediatric neurosurgery at Children’s Hospital of Pittsburgh Brain Care Institute, and his colleagues have enrolled 27 human leukocyte antigen (HLA) A2–positive children to date, including 16 who are newly diagnosed with brain stem gliomas, 5 with newly diagnosed high-grade gliomas, and 6 with recurrent gliomas. The GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13RA2), and survivin, he said.

All of the children received eight courses of subcutaneous vaccinations with peptides for GAA epitopes emulsified in Montanide-ISA-51 every 3 weeks, along with intramuscular injections of the immunoadjuvant poly-ICLC, which promotes the infiltration of effector T cells into intracranial gliomas.

"Our primary end points were safety and T-cell response against vaccine-targeted [GAAs]," he said, noting that treatment response was assessed clinically and by MRI.

The preliminary results reported at the meeting are based on an interim analysis of 22 evaluable patients. To date, no non–central nervous system toxicities have limited the vaccine dosages, Dr. Pollack said. Of the 22 children, 4 showed signs of rapidly progressive disease, 14 had stable disease for more than 3 months, 3 had sustained partial responses, and 1 had prolonged disease-free status after surgery, he reported.

Symptomatic "pseudoprogression" – consisting of transient neurologic deterioration and tumor enlargement, followed by tumor regression and stabilization on decreasing steroid doses with sustained partial response – was observed in four of the children with brain stem glioma, said Dr. Pollack, who is also codirector of the University of Pittsburgh Cancer Institute’s brain tumor program.

Results of the ELISPOT (enzyme-linked immunosorbent spot) assay, which was completed in seven of the children, showed responses in six of them. Specifically, the investigators observed responses to IL-13RA2 in five cases, EphA2 in three cases, and survivin in three cases, Dr. Pollack said.

"Based on what we’ve seen so far, it seems that these kids are able to mount immune responses to the vaccine at high rates, possibly higher than we’ve seen in adult studies," likely because of their robust immune systems, he said in an interview.

The observation of immunologic and clinical response – particularly the evidence of tumor shrinkage in children with very high-risk tumors – "has been extremely encouraging and somewhat surprising," Dr. Pollack reported. "This is the first study of its type that examined peptide vaccine therapy for children with brain tumors like this."

The findings are especially notable because children with these tumors generally do not respond well to standard chemotherapy, he said, stressing that if further study validates the early findings, "immunotherapy may be a promising strategy to control tumor growth."

The study was funded by the National Institutes of Health. Dr. Pollack disclosed having no potential conflicts of interest.

An MR spectroscopic imaging technique has the potential to predict the prognosis and response to treatment of patients with low-grade infiltrating gliomas that harbor mutations in the gene encoding isocitrate dehydrogenase 1, according to ex vivo and in vivo imaging studies.

The approach takes advantage of experimental results that show the production and accumulation of 2-hydroxyglutarate (2HG) is a consequence of new enzymatic activity of mutant IDH1 variants that are present in more than 70% of patients with low-grade gliomas and have a better than 5-year survival rate than do wild-type IDH1 gliomas. The metabolite is found in a high enough concentration for new MR spectroscopic methods to differentiate it in vivo from the overlapping spectra of metabolites with similar chemical shifts.

The studies suggest great potential for such imaging tests if the biological rationale for such an approach can be verified in animal studies and much larger validation studies, Dr. Patrick Y. Wen said in an interview.

"Being able to measure 2HG in patients noninvasively with MR spectroscopy opens up a whole lot of options. You could diagnose patients. It would help in the diagnosis of the tumor itself, and it would give you an idea of the type of tumor and the prognosis. There are also companies making drugs against IDH, and so you could now noninvasively identify those patients who would be suitable for these drugs," said Dr. Wen, director of the division of neuro-oncology at Brigham and Women’s Hospital, Boston. He was not involved in the studies.

In one study, Adam Elkhaled and his colleagues at the University of California, San Francisco, examined 104 tissue samples from 52 patients who had previously been diagnosed with World Health Organization grade II glioma but were presenting for surgical resection because of suspected disease recurrence (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002796]).

They used proton high-resolution magic angle spinning nuclear MR spectroscopy to evaluate the samples for the presence of 2HG. Spectra were positive for 2HG in 33 of 38 patients with evaluable samples (58 of 66 tissue specimens), which translated to a concordance of 86% between the presence of 2HG in tissue samples (51 of 59) and positive IDH1 mutation status (32 of 38).

The investigators found positive correlations in the tissue specimens between 2HG levels and other metabolites that are commonly associated with tumor, as well as with common findings in tumor tissue histopathology, such as mitotic activity, relative tumor content, and cellular density, which "implies that in vivo levels of 2HG may be able to contribute not only to the classification of glioma but also to characterizing the spatial extent of infiltrative lesions," Mr. Elkhaled and his colleagues wrote. The results also suggest that the presence of 2HG may help in "determining the extent of recurrent tumor in an in vivo setting," especially when differentiating tumor from treatment effects.

Dr. Ovidiu C. Andronesi of Massachusetts General Hospital, Boston, and colleagues took these ex vivo findings a step further by applying a two-dimensional correlation MR spectroscopy technique that is able to resolve 2HG from similar metabolites, such as glutamate and glutamine (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002693]).

In a preliminary study, they applied the technique to determine the presence of 2HG and measure its level relative to the amounts of glutamate and glutamine present in vivo in two glioma patients with an IDH1 mutation and eight control patients with wild-type IDH1 (including four with primary glioblastoma and four healthy volunteers). The two-dimensional technique correctly identified 2HG in the two patients with IDH1 mutations and did not find 2HG – as expected – in the patients with wild-type IDH1.

Pharmaceutical companies are interested in developing inhibitors of mutated IDH1, Dr. Andronesi and his associates noted, because 2HG might act as an oncometabolite that competitively inhibits enzymes involved in altering histone proteins and DNA methylation, as well as enzymes that affect the level of hypoxia-inducible factor 1, which may be involved in tumor angiogenesis and growth.

Many patients’ low-grade gliomas eventually recur, but not all will get another biopsy, which is where Dr. Wen thought the ability to monitor 2HG levels noninvasively would be of value, particularly in measuring its levels in patients taking inhibitors of mutant IDH. He noted that falling 2HG levels in these patients could be a biomarker response, which "opens up a whole number of options that have never previously been possible in brain tumors because we haven’t had such a biomarker before."

Both studies were funded by grants from the National Institutes of Health. Dr. Andronesi also received support from the Harvard Catalyst (the Harvard Clinical and Translational Science Center).

Dr. Andronesi and a coauthor have applied for a patent for the two-dimensional MRS method they used in their study. No other authors for either study reported having relevant disclosures. Dr. Wen said that he had no relevant disclosures.

An MR spectroscopic imaging technique has the potential to predict the prognosis and response to treatment of patients with low-grade infiltrating gliomas that harbor mutations in the gene encoding isocitrate dehydrogenase 1, according to ex vivo and in vivo imaging studies.

The approach takes advantage of experimental results that show the production and accumulation of 2-hydroxyglutarate (2HG) is a consequence of new enzymatic activity of mutant IDH1 variants that are present in more than 70% of patients with low-grade gliomas and have a better than 5-year survival rate than do wild-type IDH1 gliomas. The metabolite is found in a high enough concentration for new MR spectroscopic methods to differentiate it in vivo from the overlapping spectra of metabolites with similar chemical shifts.

The studies suggest great potential for such imaging tests if the biological rationale for such an approach can be verified in animal studies and much larger validation studies, Dr. Patrick Y. Wen said in an interview.

"Being able to measure 2HG in patients noninvasively with MR spectroscopy opens up a whole lot of options. You could diagnose patients. It would help in the diagnosis of the tumor itself, and it would give you an idea of the type of tumor and the prognosis. There are also companies making drugs against IDH, and so you could now noninvasively identify those patients who would be suitable for these drugs," said Dr. Wen, director of the division of neuro-oncology at Brigham and Women’s Hospital, Boston. He was not involved in the studies.

In one study, Adam Elkhaled and his colleagues at the University of California, San Francisco, examined 104 tissue samples from 52 patients who had previously been diagnosed with World Health Organization grade II glioma but were presenting for surgical resection because of suspected disease recurrence (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002796]).

They used proton high-resolution magic angle spinning nuclear MR spectroscopy to evaluate the samples for the presence of 2HG. Spectra were positive for 2HG in 33 of 38 patients with evaluable samples (58 of 66 tissue specimens), which translated to a concordance of 86% between the presence of 2HG in tissue samples (51 of 59) and positive IDH1 mutation status (32 of 38).

The investigators found positive correlations in the tissue specimens between 2HG levels and other metabolites that are commonly associated with tumor, as well as with common findings in tumor tissue histopathology, such as mitotic activity, relative tumor content, and cellular density, which "implies that in vivo levels of 2HG may be able to contribute not only to the classification of glioma but also to characterizing the spatial extent of infiltrative lesions," Mr. Elkhaled and his colleagues wrote. The results also suggest that the presence of 2HG may help in "determining the extent of recurrent tumor in an in vivo setting," especially when differentiating tumor from treatment effects.

Dr. Ovidiu C. Andronesi of Massachusetts General Hospital, Boston, and colleagues took these ex vivo findings a step further by applying a two-dimensional correlation MR spectroscopy technique that is able to resolve 2HG from similar metabolites, such as glutamate and glutamine (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002693]).

In a preliminary study, they applied the technique to determine the presence of 2HG and measure its level relative to the amounts of glutamate and glutamine present in vivo in two glioma patients with an IDH1 mutation and eight control patients with wild-type IDH1 (including four with primary glioblastoma and four healthy volunteers). The two-dimensional technique correctly identified 2HG in the two patients with IDH1 mutations and did not find 2HG – as expected – in the patients with wild-type IDH1.

Pharmaceutical companies are interested in developing inhibitors of mutated IDH1, Dr. Andronesi and his associates noted, because 2HG might act as an oncometabolite that competitively inhibits enzymes involved in altering histone proteins and DNA methylation, as well as enzymes that affect the level of hypoxia-inducible factor 1, which may be involved in tumor angiogenesis and growth.

Many patients’ low-grade gliomas eventually recur, but not all will get another biopsy, which is where Dr. Wen thought the ability to monitor 2HG levels noninvasively would be of value, particularly in measuring its levels in patients taking inhibitors of mutant IDH. He noted that falling 2HG levels in these patients could be a biomarker response, which "opens up a whole number of options that have never previously been possible in brain tumors because we haven’t had such a biomarker before."

Both studies were funded by grants from the National Institutes of Health. Dr. Andronesi also received support from the Harvard Catalyst (the Harvard Clinical and Translational Science Center).

Dr. Andronesi and a coauthor have applied for a patent for the two-dimensional MRS method they used in their study. No other authors for either study reported having relevant disclosures. Dr. Wen said that he had no relevant disclosures.

An MR spectroscopic imaging technique has the potential to predict the prognosis and response to treatment of patients with low-grade infiltrating gliomas that harbor mutations in the gene encoding isocitrate dehydrogenase 1, according to ex vivo and in vivo imaging studies.

The approach takes advantage of experimental results that show the production and accumulation of 2-hydroxyglutarate (2HG) is a consequence of new enzymatic activity of mutant IDH1 variants that are present in more than 70% of patients with low-grade gliomas and have a better than 5-year survival rate than do wild-type IDH1 gliomas. The metabolite is found in a high enough concentration for new MR spectroscopic methods to differentiate it in vivo from the overlapping spectra of metabolites with similar chemical shifts.

The studies suggest great potential for such imaging tests if the biological rationale for such an approach can be verified in animal studies and much larger validation studies, Dr. Patrick Y. Wen said in an interview.

"Being able to measure 2HG in patients noninvasively with MR spectroscopy opens up a whole lot of options. You could diagnose patients. It would help in the diagnosis of the tumor itself, and it would give you an idea of the type of tumor and the prognosis. There are also companies making drugs against IDH, and so you could now noninvasively identify those patients who would be suitable for these drugs," said Dr. Wen, director of the division of neuro-oncology at Brigham and Women’s Hospital, Boston. He was not involved in the studies.

In one study, Adam Elkhaled and his colleagues at the University of California, San Francisco, examined 104 tissue samples from 52 patients who had previously been diagnosed with World Health Organization grade II glioma but were presenting for surgical resection because of suspected disease recurrence (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002796]).

They used proton high-resolution magic angle spinning nuclear MR spectroscopy to evaluate the samples for the presence of 2HG. Spectra were positive for 2HG in 33 of 38 patients with evaluable samples (58 of 66 tissue specimens), which translated to a concordance of 86% between the presence of 2HG in tissue samples (51 of 59) and positive IDH1 mutation status (32 of 38).

The investigators found positive correlations in the tissue specimens between 2HG levels and other metabolites that are commonly associated with tumor, as well as with common findings in tumor tissue histopathology, such as mitotic activity, relative tumor content, and cellular density, which "implies that in vivo levels of 2HG may be able to contribute not only to the classification of glioma but also to characterizing the spatial extent of infiltrative lesions," Mr. Elkhaled and his colleagues wrote. The results also suggest that the presence of 2HG may help in "determining the extent of recurrent tumor in an in vivo setting," especially when differentiating tumor from treatment effects.

Dr. Ovidiu C. Andronesi of Massachusetts General Hospital, Boston, and colleagues took these ex vivo findings a step further by applying a two-dimensional correlation MR spectroscopy technique that is able to resolve 2HG from similar metabolites, such as glutamate and glutamine (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002693]).

In a preliminary study, they applied the technique to determine the presence of 2HG and measure its level relative to the amounts of glutamate and glutamine present in vivo in two glioma patients with an IDH1 mutation and eight control patients with wild-type IDH1 (including four with primary glioblastoma and four healthy volunteers). The two-dimensional technique correctly identified 2HG in the two patients with IDH1 mutations and did not find 2HG – as expected – in the patients with wild-type IDH1.

Pharmaceutical companies are interested in developing inhibitors of mutated IDH1, Dr. Andronesi and his associates noted, because 2HG might act as an oncometabolite that competitively inhibits enzymes involved in altering histone proteins and DNA methylation, as well as enzymes that affect the level of hypoxia-inducible factor 1, which may be involved in tumor angiogenesis and growth.

Many patients’ low-grade gliomas eventually recur, but not all will get another biopsy, which is where Dr. Wen thought the ability to monitor 2HG levels noninvasively would be of value, particularly in measuring its levels in patients taking inhibitors of mutant IDH. He noted that falling 2HG levels in these patients could be a biomarker response, which "opens up a whole number of options that have never previously been possible in brain tumors because we haven’t had such a biomarker before."

Both studies were funded by grants from the National Institutes of Health. Dr. Andronesi also received support from the Harvard Catalyst (the Harvard Clinical and Translational Science Center).

Dr. Andronesi and a coauthor have applied for a patent for the two-dimensional MRS method they used in their study. No other authors for either study reported having relevant disclosures. Dr. Wen said that he had no relevant disclosures.

BALTIMORE – Gamma Knife surgery significantly reduced the number of seizures in a subset of patients with rare congenital tumors, based on data from a prospective trial of 64 patients presented at the annual meeting of the American Epilepsy Society.

Hypothalamic hamartomas (congenital tumors that are attached to functional brain tissue) can cause a range of complications, including intractable seizures, said Dr. Jean Régis of Timone University Hospital in Marseilles, France.

Dr. Régis’s center is one of the few in the world where Gamma Knife surgery is performed on patients with hypothalamic hamartomas (HH). His ongoing study includes patients as young as age 3 years who have undergone surgery for HH. After a median of 62 months’ follow-up, the number of seizures in this group dropped from a median of 92 per month to a median of 6 per month.

But the benefits of the surgery extended beyond seizure reduction, Dr. Régis emphasized. Global psychiatric and cognitive comorbidity was considered cured in 28% of patients, improved in 56% of patients, and stable in 8% of patients at postsurgical follow-up.

Hyperkinetic behavior was identified in 34 patients at baseline. After surgery, 35% of patients were cured of hyperkinetic behavior and 30% were very much improved, Dr. Régis said. In addition, heteroaggressive behavior was noted in 56 patients at baseline, but after surgery, the behavior completely disappeared in 53% of these patients and was dramatically reduced in 32%, he added.

The specific approach for Gamma Knife surgery depends on the anatomy of the lesion, Dr. Régis noted. Most of the patients in this study had hamartomas of types I-IV, which are the smaller lesions, he said. The median marginal dose of radiation was 17 Gy and the median volume was 419 mm³.

"Longer follow-up remains mandatory due to the young age of this population," Dr. Régis said.

"Beyond seizure reduction, the improvement of the psychiatric, cognitive condition, and school and social insertion is turning out to be the major benefit of GKS in this frequently catastrophic epilepsy group," he added.

Dr. Régis is the president of the International Stereotactic Radiosurgery Society (ISRS) and chairman of its 2011 congress. He said he has raised major congress funding from the following manufacturers of radiosurgery devices: Accuray, BrainLab, Elekta, and Radionic.

BALTIMORE – Gamma Knife surgery significantly reduced the number of seizures in a subset of patients with rare congenital tumors, based on data from a prospective trial of 64 patients presented at the annual meeting of the American Epilepsy Society.

Hypothalamic hamartomas (congenital tumors that are attached to functional brain tissue) can cause a range of complications, including intractable seizures, said Dr. Jean Régis of Timone University Hospital in Marseilles, France.

Dr. Régis’s center is one of the few in the world where Gamma Knife surgery is performed on patients with hypothalamic hamartomas (HH). His ongoing study includes patients as young as age 3 years who have undergone surgery for HH. After a median of 62 months’ follow-up, the number of seizures in this group dropped from a median of 92 per month to a median of 6 per month.

But the benefits of the surgery extended beyond seizure reduction, Dr. Régis emphasized. Global psychiatric and cognitive comorbidity was considered cured in 28% of patients, improved in 56% of patients, and stable in 8% of patients at postsurgical follow-up.

Hyperkinetic behavior was identified in 34 patients at baseline. After surgery, 35% of patients were cured of hyperkinetic behavior and 30% were very much improved, Dr. Régis said. In addition, heteroaggressive behavior was noted in 56 patients at baseline, but after surgery, the behavior completely disappeared in 53% of these patients and was dramatically reduced in 32%, he added.

The specific approach for Gamma Knife surgery depends on the anatomy of the lesion, Dr. Régis noted. Most of the patients in this study had hamartomas of types I-IV, which are the smaller lesions, he said. The median marginal dose of radiation was 17 Gy and the median volume was 419 mm³.

"Longer follow-up remains mandatory due to the young age of this population," Dr. Régis said.

"Beyond seizure reduction, the improvement of the psychiatric, cognitive condition, and school and social insertion is turning out to be the major benefit of GKS in this frequently catastrophic epilepsy group," he added.

Dr. Régis is the president of the International Stereotactic Radiosurgery Society (ISRS) and chairman of its 2011 congress. He said he has raised major congress funding from the following manufacturers of radiosurgery devices: Accuray, BrainLab, Elekta, and Radionic.

BALTIMORE – Gamma Knife surgery significantly reduced the number of seizures in a subset of patients with rare congenital tumors, based on data from a prospective trial of 64 patients presented at the annual meeting of the American Epilepsy Society.

Hypothalamic hamartomas (congenital tumors that are attached to functional brain tissue) can cause a range of complications, including intractable seizures, said Dr. Jean Régis of Timone University Hospital in Marseilles, France.

Dr. Régis’s center is one of the few in the world where Gamma Knife surgery is performed on patients with hypothalamic hamartomas (HH). His ongoing study includes patients as young as age 3 years who have undergone surgery for HH. After a median of 62 months’ follow-up, the number of seizures in this group dropped from a median of 92 per month to a median of 6 per month.

But the benefits of the surgery extended beyond seizure reduction, Dr. Régis emphasized. Global psychiatric and cognitive comorbidity was considered cured in 28% of patients, improved in 56% of patients, and stable in 8% of patients at postsurgical follow-up.

Hyperkinetic behavior was identified in 34 patients at baseline. After surgery, 35% of patients were cured of hyperkinetic behavior and 30% were very much improved, Dr. Régis said. In addition, heteroaggressive behavior was noted in 56 patients at baseline, but after surgery, the behavior completely disappeared in 53% of these patients and was dramatically reduced in 32%, he added.

The specific approach for Gamma Knife surgery depends on the anatomy of the lesion, Dr. Régis noted. Most of the patients in this study had hamartomas of types I-IV, which are the smaller lesions, he said. The median marginal dose of radiation was 17 Gy and the median volume was 419 mm³.

"Longer follow-up remains mandatory due to the young age of this population," Dr. Régis said.

"Beyond seizure reduction, the improvement of the psychiatric, cognitive condition, and school and social insertion is turning out to be the major benefit of GKS in this frequently catastrophic epilepsy group," he added.

Dr. Régis is the president of the International Stereotactic Radiosurgery Society (ISRS) and chairman of its 2011 congress. He said he has raised major congress funding from the following manufacturers of radiosurgery devices: Accuray, BrainLab, Elekta, and Radionic.

MIAMI BEACH – Where conventional radiation and surgery often fail, high-dose proton–based radiation therapy can succeed at providing local control of spinal chordomas, according to investigators at the annual meeting of the American Society for Radiation Oncology.

Among 126 patients with 127 localized chordomas, those who received a combination of pre- and postoperative radiation with protons added to photon radiation had a 5-year local control rate of 85%, reported Dr. Ronny L. Rotondo of the Stephen Harris Chordoma Center at Massachusetts General Hospital in Boston and his colleagues.

"Local control of spinal chordomas remains quite poor with surgery and photon-radiation therapy at conventional doses less than 60 Gy, with a number of series reporting local failure rates as high as 75%-100%. More recently, a number of centers have reported encouraging results with particle therapy, including protons and carbon ions," Dr. Rotondo said.

Chordomas are rare cancers that arise from the remnants of the fetal notochord, a structure that normally exists only during embryonic development. Although they do not tend to metastasize, chordomas incapacitate patients with locally aggressive growth.

Surgical resection is the mainstay of treatment, but local recurrences are common, and salvage therapy after local failure is often unsuccessful, hence the need for adjuvant radiation therapy, Dr. Rotondo said.

The unique physical properties of proton energy deposition in tissue makes proton therapy well suited for treatment of chordomas; most of the dose is deposited in the target tissue with little or no exit dose, allowing for higher doses and better local control than is possible with conventional photon therapy, he said.

He and his colleagues looked at clinical outcomes and clinical and pathologic prognostic factors in patients who underwent high-dose proton–based therapy with or without surgery for primary or recurrent chordomas of the thoracic, lumbar, or sacrococcygeal spine.

The patients were treated from 1982 through 2011 at either the Harvard Cyclotron Laboratory in Cambridge, Mass., or more recently at Massachusetts General Hospital’s proton therapy center in Boston. Their mean age at diagnosis was 53 years (range, 5-88 years), and the mean maximum size of lesions was 7 cm (range, 1.6 cm-21.7 cm).

In all, 45% of patients had surgery followed by radiation; 48% had preoperative radiation and surgery, followed by postoperative radiation; and 7% had radiation for recurrent tumors. About half of all of the surgeries (49%) were performed with en bloc resection, and 49% were intralesional (in the remaining 2% the surgery type was unknown).

Clear surgical margins (R0) were achieved in 27% of patients, with 45% having R1 resections, 24% having R2 margins, and 4% having unknown margin status.

Although some received protons* exclusively, most patients received a combination of photons and protons, with the protons comprising about 45% of the energy delivered in both pre- and postoperative treatment. The mean total dose delivered was 72.4 Gy.

Among patients still alive, median follow-up was 47 months with a median of 5.7 months since the last follow-up.

For the entire cohort, overall survival was 81% at 5 years and 53% at 10 years. The local control rate was 62% at 5 years and 49% at 10 years. Distant control was 77% at 5 years and 63% at 10 years.

Comparing patients by presentation, the investigators found that the 5-year local rate was 68% for patients with primary tumors, compared with 49% for those with recurrent tumors (P = .058). Respective 5-year event-free survival rates by presentation were 51% and 34% (P = .035).

Local control rates were also significantly better among patients who had undergone en bloc resection, at 72% at 5 years, compared with 55% for those who underwent an intralesional procedure (P = .016).

There were no significant differences in local control by surgical margin size, although there was a trend favoring R0, compared with R1 or R2, resections.

Preoperative radiotherapy also offered a significant benefit in both local and locoregional control of primary tumors. Local control at 5 years was 85% for those who received preoperative radiation in addition to postoperative, compared with 56% for those who did not (P = .019). Respective locoregional control rates were 79% and 56% at 5 years (P = .034).

The review was internally funded. Dr. Rotondo reported having no relevant conflicts of interest.

*Correction, 10/25/2011: An earlier version of this story incorrectly stated that some patients received photons exclusively.

MIAMI BEACH – Where conventional radiation and surgery often fail, high-dose proton–based radiation therapy can succeed at providing local control of spinal chordomas, according to investigators at the annual meeting of the American Society for Radiation Oncology.

Among 126 patients with 127 localized chordomas, those who received a combination of pre- and postoperative radiation with protons added to photon radiation had a 5-year local control rate of 85%, reported Dr. Ronny L. Rotondo of the Stephen Harris Chordoma Center at Massachusetts General Hospital in Boston and his colleagues.

"Local control of spinal chordomas remains quite poor with surgery and photon-radiation therapy at conventional doses less than 60 Gy, with a number of series reporting local failure rates as high as 75%-100%. More recently, a number of centers have reported encouraging results with particle therapy, including protons and carbon ions," Dr. Rotondo said.

Chordomas are rare cancers that arise from the remnants of the fetal notochord, a structure that normally exists only during embryonic development. Although they do not tend to metastasize, chordomas incapacitate patients with locally aggressive growth.

Surgical resection is the mainstay of treatment, but local recurrences are common, and salvage therapy after local failure is often unsuccessful, hence the need for adjuvant radiation therapy, Dr. Rotondo said.

The unique physical properties of proton energy deposition in tissue makes proton therapy well suited for treatment of chordomas; most of the dose is deposited in the target tissue with little or no exit dose, allowing for higher doses and better local control than is possible with conventional photon therapy, he said.

He and his colleagues looked at clinical outcomes and clinical and pathologic prognostic factors in patients who underwent high-dose proton–based therapy with or without surgery for primary or recurrent chordomas of the thoracic, lumbar, or sacrococcygeal spine.

The patients were treated from 1982 through 2011 at either the Harvard Cyclotron Laboratory in Cambridge, Mass., or more recently at Massachusetts General Hospital’s proton therapy center in Boston. Their mean age at diagnosis was 53 years (range, 5-88 years), and the mean maximum size of lesions was 7 cm (range, 1.6 cm-21.7 cm).

In all, 45% of patients had surgery followed by radiation; 48% had preoperative radiation and surgery, followed by postoperative radiation; and 7% had radiation for recurrent tumors. About half of all of the surgeries (49%) were performed with en bloc resection, and 49% were intralesional (in the remaining 2% the surgery type was unknown).

Clear surgical margins (R0) were achieved in 27% of patients, with 45% having R1 resections, 24% having R2 margins, and 4% having unknown margin status.

Although some received protons* exclusively, most patients received a combination of photons and protons, with the protons comprising about 45% of the energy delivered in both pre- and postoperative treatment. The mean total dose delivered was 72.4 Gy.

Among patients still alive, median follow-up was 47 months with a median of 5.7 months since the last follow-up.

For the entire cohort, overall survival was 81% at 5 years and 53% at 10 years. The local control rate was 62% at 5 years and 49% at 10 years. Distant control was 77% at 5 years and 63% at 10 years.

Comparing patients by presentation, the investigators found that the 5-year local rate was 68% for patients with primary tumors, compared with 49% for those with recurrent tumors (P = .058). Respective 5-year event-free survival rates by presentation were 51% and 34% (P = .035).

Local control rates were also significantly better among patients who had undergone en bloc resection, at 72% at 5 years, compared with 55% for those who underwent an intralesional procedure (P = .016).

There were no significant differences in local control by surgical margin size, although there was a trend favoring R0, compared with R1 or R2, resections.

Preoperative radiotherapy also offered a significant benefit in both local and locoregional control of primary tumors. Local control at 5 years was 85% for those who received preoperative radiation in addition to postoperative, compared with 56% for those who did not (P = .019). Respective locoregional control rates were 79% and 56% at 5 years (P = .034).

The review was internally funded. Dr. Rotondo reported having no relevant conflicts of interest.

*Correction, 10/25/2011: An earlier version of this story incorrectly stated that some patients received photons exclusively.

MIAMI BEACH – Where conventional radiation and surgery often fail, high-dose proton–based radiation therapy can succeed at providing local control of spinal chordomas, according to investigators at the annual meeting of the American Society for Radiation Oncology.

Among 126 patients with 127 localized chordomas, those who received a combination of pre- and postoperative radiation with protons added to photon radiation had a 5-year local control rate of 85%, reported Dr. Ronny L. Rotondo of the Stephen Harris Chordoma Center at Massachusetts General Hospital in Boston and his colleagues.

"Local control of spinal chordomas remains quite poor with surgery and photon-radiation therapy at conventional doses less than 60 Gy, with a number of series reporting local failure rates as high as 75%-100%. More recently, a number of centers have reported encouraging results with particle therapy, including protons and carbon ions," Dr. Rotondo said.

Chordomas are rare cancers that arise from the remnants of the fetal notochord, a structure that normally exists only during embryonic development. Although they do not tend to metastasize, chordomas incapacitate patients with locally aggressive growth.

Surgical resection is the mainstay of treatment, but local recurrences are common, and salvage therapy after local failure is often unsuccessful, hence the need for adjuvant radiation therapy, Dr. Rotondo said.

The unique physical properties of proton energy deposition in tissue makes proton therapy well suited for treatment of chordomas; most of the dose is deposited in the target tissue with little or no exit dose, allowing for higher doses and better local control than is possible with conventional photon therapy, he said.

He and his colleagues looked at clinical outcomes and clinical and pathologic prognostic factors in patients who underwent high-dose proton–based therapy with or without surgery for primary or recurrent chordomas of the thoracic, lumbar, or sacrococcygeal spine.

The patients were treated from 1982 through 2011 at either the Harvard Cyclotron Laboratory in Cambridge, Mass., or more recently at Massachusetts General Hospital’s proton therapy center in Boston. Their mean age at diagnosis was 53 years (range, 5-88 years), and the mean maximum size of lesions was 7 cm (range, 1.6 cm-21.7 cm).

In all, 45% of patients had surgery followed by radiation; 48% had preoperative radiation and surgery, followed by postoperative radiation; and 7% had radiation for recurrent tumors. About half of all of the surgeries (49%) were performed with en bloc resection, and 49% were intralesional (in the remaining 2% the surgery type was unknown).

Clear surgical margins (R0) were achieved in 27% of patients, with 45% having R1 resections, 24% having R2 margins, and 4% having unknown margin status.

Although some received protons* exclusively, most patients received a combination of photons and protons, with the protons comprising about 45% of the energy delivered in both pre- and postoperative treatment. The mean total dose delivered was 72.4 Gy.

Among patients still alive, median follow-up was 47 months with a median of 5.7 months since the last follow-up.

For the entire cohort, overall survival was 81% at 5 years and 53% at 10 years. The local control rate was 62% at 5 years and 49% at 10 years. Distant control was 77% at 5 years and 63% at 10 years.

Comparing patients by presentation, the investigators found that the 5-year local rate was 68% for patients with primary tumors, compared with 49% for those with recurrent tumors (P = .058). Respective 5-year event-free survival rates by presentation were 51% and 34% (P = .035).

Local control rates were also significantly better among patients who had undergone en bloc resection, at 72% at 5 years, compared with 55% for those who underwent an intralesional procedure (P = .016).

There were no significant differences in local control by surgical margin size, although there was a trend favoring R0, compared with R1 or R2, resections.

Preoperative radiotherapy also offered a significant benefit in both local and locoregional control of primary tumors. Local control at 5 years was 85% for those who received preoperative radiation in addition to postoperative, compared with 56% for those who did not (P = .019). Respective locoregional control rates were 79% and 56% at 5 years (P = .034).

The review was internally funded. Dr. Rotondo reported having no relevant conflicts of interest.

*Correction, 10/25/2011: An earlier version of this story incorrectly stated that some patients received photons exclusively.

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

Most patients with glioma (80%) experience at least one seizure during the course of their illness, but about one-third have recurrent seizures, known as tumor-associated epilepsy, that are often refractory to antiepileptic drugs, the investigators said.

Dr. Buckingham and her colleagues detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration-approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators "that system x_c- does not contribute substantially to glutamate release in tumor-free brain." Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

"Together with previous studies, our findings establish that system x_c- is a viable new target for seizure treatments," the authors concluded.

SAS did not inhibit tumor growth in an earlier clinical trial involving end-stage glioblastoma patients with poor neurological status, but the study did not assess its antiepileptic effects. Because "seizures often present early in disease progression, particularly among patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs," the investigators noted that such patients "would be most likely to benefit from SAS treatment" in a clinical trial.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is "primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures." The trial will use chemical shift MRI to determine the acute effect of oral sulfasalazine on glutamate release. A phase I trial in a several patients has already generated data showing that the treatment is feasible, Dr. Sontheimer said.

The current study was funded by grants from the National Institutes of Health. None of the authors had relevant financial disclosures.

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

Most patients with glioma (80%) experience at least one seizure during the course of their illness, but about one-third have recurrent seizures, known as tumor-associated epilepsy, that are often refractory to antiepileptic drugs, the investigators said.

Dr. Buckingham and her colleagues detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration-approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators "that system x_c- does not contribute substantially to glutamate release in tumor-free brain." Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

"Together with previous studies, our findings establish that system x_c- is a viable new target for seizure treatments," the authors concluded.

SAS did not inhibit tumor growth in an earlier clinical trial involving end-stage glioblastoma patients with poor neurological status, but the study did not assess its antiepileptic effects. Because "seizures often present early in disease progression, particularly among patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs," the investigators noted that such patients "would be most likely to benefit from SAS treatment" in a clinical trial.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is "primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures." The trial will use chemical shift MRI to determine the acute effect of oral sulfasalazine on glutamate release. A phase I trial in a several patients has already generated data showing that the treatment is feasible, Dr. Sontheimer said.

The current study was funded by grants from the National Institutes of Health. None of the authors had relevant financial disclosures.

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

Most patients with glioma (80%) experience at least one seizure during the course of their illness, but about one-third have recurrent seizures, known as tumor-associated epilepsy, that are often refractory to antiepileptic drugs, the investigators said.

Dr. Buckingham and her colleagues detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration-approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators "that system x_c- does not contribute substantially to glutamate release in tumor-free brain." Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

"Together with previous studies, our findings establish that system x_c- is a viable new target for seizure treatments," the authors concluded.

SAS did not inhibit tumor growth in an earlier clinical trial involving end-stage glioblastoma patients with poor neurological status, but the study did not assess its antiepileptic effects. Because "seizures often present early in disease progression, particularly among patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs," the investigators noted that such patients "would be most likely to benefit from SAS treatment" in a clinical trial.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is "primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures." The trial will use chemical shift MRI to determine the acute effect of oral sulfasalazine on glutamate release. A phase I trial in a several patients has already generated data showing that the treatment is feasible, Dr. Sontheimer said.

The current study was funded by grants from the National Institutes of Health. None of the authors had relevant financial disclosures.

CHICAGO – Dose-dense temozolomide was no more effective than standard adjuvant temozolomide for patients with newly diagnosed glioblastoma in the randomized, phase III Radiation Treatment Oncology Group 0525 study.

Among 833 patients, the primary end point of median overall survival was 16.6 months with standard temozolomide (Temodar) vs. 14.9 months with dose-dense temozolomide (P = .63; hazard ratio 0.87).

Median progression-free survival was also similar at 5.5 months vs. 6.7 months (P = .06; HR, 0.87), Dr. Mark R. Gilbert reported at the meeting

RTOG 0525 was designed as a successor to the landmark EORTC (European Organisation for Research and Treatment of Cancer) trial that helped establish radiation plus concomitant and adjuvant temozolomide as the international standard of care for newly diagnosed glioblastoma (N. Engl. J. Med. 2005;352:987-96). It also helped to identify patients with MGMT (O⁶-methylguanine-DNA methyltransferase)–methylated tumors as a subpopulation that appeared to derive greater benefit from temozolomide (N. Engl. J. Med. 2005;352:997-1003).

It was hoped that dose-dense therapy would further enhance the efficacy of temozolomide in MGMT-methylated tumors and would deplete the endogenous reservoir of MGMT in nonmethylated MGMT tumors, as well as induce sensitivity to temozolomide, an oral alkylating agent. The MGMT gene encodes a DNA repair enzyme that can cancel the effects of alkylating chemotherapy.

Although the therapeutic end point was not reached, the study confirmed the prognostic value of MGMT promoter methylation status, said Dr. Gilbert, a professor of neuro-oncology at the University of Texas M.D. AndersonCancer Center in Houston.

MGMT-methylated tumors, compared with unmethylated tumors, were associated with significant improvements in median overall survival (21.2 months vs. 14 months; P less than .0001; HR, 1.74) and progression-free survival (8.7 months vs. 5.7 months; P less than .0001; HR, 1.63).

However, MGMT methylation status did not predict response to the dose-dense schedule, he said. No significant differences in overall or progression-free survival were observed between unmethylated and methylated tumors, regardless of treatment with standard or dose-dense temozolomide.

A Cox proportional hazard model showed that MGMT status and recursive partitioning analysis (RPA) class IV vs. III were significant predictors of overall and progression-free survival, whereas the treatment arm and type of radiation therapy (EORTC vs. RTOG) were not, Dr. Gilbert said.

He observed that RTOG 0525 had a slightly different population than did the EORTC trial in that it required a surgical procedure, enrolled patients older than 70 years, and required all patients to make it through chemoradiation to be randomized.

Invited discussant Dr. Jeffrey S. Abrams of the National Cancer Institute said "We’re all disappointed that it wasn’t positive, but there’s reason to take heart."

He observed that in 2.5 years of accrual, the group conducted what is likely the largest glioblastoma study to date, had a 98% tumor tissue collection rate, and ran a very well-conducted trial in an international collaboration. RTOG 0525 was conducted at 185 North American and 24 European centers by the RTOG, EORTC, and North Central Cancer Treatment Group.

"I think this bodes well for this sort of collaborative process that will speed the development of better treatments for glioblastoma," Dr. Abrams said.

He suggested that the trial may have failed because adjuvant temozolomide is not the active part of the regimen. He pointed out that a randomized, phase II Greek trial increased adjuvant temozolomide to 150 mg/m² every 2 weeks, but saw no improvement in outcome (J. Clin. Oncol. 2005;23:2372-7) and that a small, single-institution study reported comparable survival outcomes with standard temozolomide when temozolomide was administered during the radiation phase at a lower dose of 50 mg/m² without maintenance (Strahlenther Onkol. 2005;181:372-7).

In RTOG 0525, 833 patients received concurrent radiation at 200 cGy in 30 fractions plus temozolomide 75 mg/m² daily, followed by 1:1 randomization to 6-12 cycles of standard temozolomide, starting at 150 mg/m² and escalating to 200 mg/m² if tolerated on days 1-5 of a 28-day cycle, or dose-dense temozolomide starting at 75 mg/m² and escalating to 100 mg/m² if tolerated on days 1-21 of a 28-day cycle.

Roughly one-fourth of patients were younger than 50 years old, more than half underwent total resection, and 45% had minor symptoms.

Grade 3-5 adverse events were significantly more common in the dose-dense arm, compared with the conventional arm (194 vs. 120; P less than .001), but they were mostly lymphopenia (107 vs. 51) and fatigue (33 vs. 12). No opportunistic infections occurred, Dr. Gilbert said.

The study was supported by Schering-Plough/Merck, the maker of temozolomide. Dr. Gilbert reported a consultant/advisory role with Genentech, and honoraria and research funding from Genentech and Merck. Several of his coauthors reported financial relationships with firms including Merck. Dr. Abrams reported that RTOG 0525 also receives funding from the National Cancer Institute, where he is employed. ☐

CHICAGO – Dose-dense temozolomide was no more effective than standard adjuvant temozolomide for patients with newly diagnosed glioblastoma in the randomized, phase III Radiation Treatment Oncology Group 0525 study.

Among 833 patients, the primary end point of median overall survival was 16.6 months with standard temozolomide (Temodar) vs. 14.9 months with dose-dense temozolomide (P = .63; hazard ratio 0.87).

Median progression-free survival was also similar at 5.5 months vs. 6.7 months (P = .06; HR, 0.87), Dr. Mark R. Gilbert reported at the meeting

RTOG 0525 was designed as a successor to the landmark EORTC (European Organisation for Research and Treatment of Cancer) trial that helped establish radiation plus concomitant and adjuvant temozolomide as the international standard of care for newly diagnosed glioblastoma (N. Engl. J. Med. 2005;352:987-96). It also helped to identify patients with MGMT (O⁶-methylguanine-DNA methyltransferase)–methylated tumors as a subpopulation that appeared to derive greater benefit from temozolomide (N. Engl. J. Med. 2005;352:997-1003).

It was hoped that dose-dense therapy would further enhance the efficacy of temozolomide in MGMT-methylated tumors and would deplete the endogenous reservoir of MGMT in nonmethylated MGMT tumors, as well as induce sensitivity to temozolomide, an oral alkylating agent. The MGMT gene encodes a DNA repair enzyme that can cancel the effects of alkylating chemotherapy.

Although the therapeutic end point was not reached, the study confirmed the prognostic value of MGMT promoter methylation status, said Dr. Gilbert, a professor of neuro-oncology at the University of Texas M.D. AndersonCancer Center in Houston.

MGMT-methylated tumors, compared with unmethylated tumors, were associated with significant improvements in median overall survival (21.2 months vs. 14 months; P less than .0001; HR, 1.74) and progression-free survival (8.7 months vs. 5.7 months; P less than .0001; HR, 1.63).

However, MGMT methylation status did not predict response to the dose-dense schedule, he said. No significant differences in overall or progression-free survival were observed between unmethylated and methylated tumors, regardless of treatment with standard or dose-dense temozolomide.

A Cox proportional hazard model showed that MGMT status and recursive partitioning analysis (RPA) class IV vs. III were significant predictors of overall and progression-free survival, whereas the treatment arm and type of radiation therapy (EORTC vs. RTOG) were not, Dr. Gilbert said.

He observed that RTOG 0525 had a slightly different population than did the EORTC trial in that it required a surgical procedure, enrolled patients older than 70 years, and required all patients to make it through chemoradiation to be randomized.

Invited discussant Dr. Jeffrey S. Abrams of the National Cancer Institute said "We’re all disappointed that it wasn’t positive, but there’s reason to take heart."

He observed that in 2.5 years of accrual, the group conducted what is likely the largest glioblastoma study to date, had a 98% tumor tissue collection rate, and ran a very well-conducted trial in an international collaboration. RTOG 0525 was conducted at 185 North American and 24 European centers by the RTOG, EORTC, and North Central Cancer Treatment Group.

"I think this bodes well for this sort of collaborative process that will speed the development of better treatments for glioblastoma," Dr. Abrams said.

He suggested that the trial may have failed because adjuvant temozolomide is not the active part of the regimen. He pointed out that a randomized, phase II Greek trial increased adjuvant temozolomide to 150 mg/m² every 2 weeks, but saw no improvement in outcome (J. Clin. Oncol. 2005;23:2372-7) and that a small, single-institution study reported comparable survival outcomes with standard temozolomide when temozolomide was administered during the radiation phase at a lower dose of 50 mg/m² without maintenance (Strahlenther Onkol. 2005;181:372-7).

In RTOG 0525, 833 patients received concurrent radiation at 200 cGy in 30 fractions plus temozolomide 75 mg/m² daily, followed by 1:1 randomization to 6-12 cycles of standard temozolomide, starting at 150 mg/m² and escalating to 200 mg/m² if tolerated on days 1-5 of a 28-day cycle, or dose-dense temozolomide starting at 75 mg/m² and escalating to 100 mg/m² if tolerated on days 1-21 of a 28-day cycle.

Roughly one-fourth of patients were younger than 50 years old, more than half underwent total resection, and 45% had minor symptoms.

Grade 3-5 adverse events were significantly more common in the dose-dense arm, compared with the conventional arm (194 vs. 120; P less than .001), but they were mostly lymphopenia (107 vs. 51) and fatigue (33 vs. 12). No opportunistic infections occurred, Dr. Gilbert said.

The study was supported by Schering-Plough/Merck, the maker of temozolomide. Dr. Gilbert reported a consultant/advisory role with Genentech, and honoraria and research funding from Genentech and Merck. Several of his coauthors reported financial relationships with firms including Merck. Dr. Abrams reported that RTOG 0525 also receives funding from the National Cancer Institute, where he is employed. ☐

CHICAGO – Dose-dense temozolomide was no more effective than standard adjuvant temozolomide for patients with newly diagnosed glioblastoma in the randomized, phase III Radiation Treatment Oncology Group 0525 study.

Among 833 patients, the primary end point of median overall survival was 16.6 months with standard temozolomide (Temodar) vs. 14.9 months with dose-dense temozolomide (P = .63; hazard ratio 0.87).

Median progression-free survival was also similar at 5.5 months vs. 6.7 months (P = .06; HR, 0.87), Dr. Mark R. Gilbert reported at the meeting

RTOG 0525 was designed as a successor to the landmark EORTC (European Organisation for Research and Treatment of Cancer) trial that helped establish radiation plus concomitant and adjuvant temozolomide as the international standard of care for newly diagnosed glioblastoma (N. Engl. J. Med. 2005;352:987-96). It also helped to identify patients with MGMT (O⁶-methylguanine-DNA methyltransferase)–methylated tumors as a subpopulation that appeared to derive greater benefit from temozolomide (N. Engl. J. Med. 2005;352:997-1003).

It was hoped that dose-dense therapy would further enhance the efficacy of temozolomide in MGMT-methylated tumors and would deplete the endogenous reservoir of MGMT in nonmethylated MGMT tumors, as well as induce sensitivity to temozolomide, an oral alkylating agent. The MGMT gene encodes a DNA repair enzyme that can cancel the effects of alkylating chemotherapy.

Although the therapeutic end point was not reached, the study confirmed the prognostic value of MGMT promoter methylation status, said Dr. Gilbert, a professor of neuro-oncology at the University of Texas M.D. AndersonCancer Center in Houston.

MGMT-methylated tumors, compared with unmethylated tumors, were associated with significant improvements in median overall survival (21.2 months vs. 14 months; P less than .0001; HR, 1.74) and progression-free survival (8.7 months vs. 5.7 months; P less than .0001; HR, 1.63).

However, MGMT methylation status did not predict response to the dose-dense schedule, he said. No significant differences in overall or progression-free survival were observed between unmethylated and methylated tumors, regardless of treatment with standard or dose-dense temozolomide.

A Cox proportional hazard model showed that MGMT status and recursive partitioning analysis (RPA) class IV vs. III were significant predictors of overall and progression-free survival, whereas the treatment arm and type of radiation therapy (EORTC vs. RTOG) were not, Dr. Gilbert said.

He observed that RTOG 0525 had a slightly different population than did the EORTC trial in that it required a surgical procedure, enrolled patients older than 70 years, and required all patients to make it through chemoradiation to be randomized.

Invited discussant Dr. Jeffrey S. Abrams of the National Cancer Institute said "We’re all disappointed that it wasn’t positive, but there’s reason to take heart."

He observed that in 2.5 years of accrual, the group conducted what is likely the largest glioblastoma study to date, had a 98% tumor tissue collection rate, and ran a very well-conducted trial in an international collaboration. RTOG 0525 was conducted at 185 North American and 24 European centers by the RTOG, EORTC, and North Central Cancer Treatment Group.

"I think this bodes well for this sort of collaborative process that will speed the development of better treatments for glioblastoma," Dr. Abrams said.

He suggested that the trial may have failed because adjuvant temozolomide is not the active part of the regimen. He pointed out that a randomized, phase II Greek trial increased adjuvant temozolomide to 150 mg/m² every 2 weeks, but saw no improvement in outcome (J. Clin. Oncol. 2005;23:2372-7) and that a small, single-institution study reported comparable survival outcomes with standard temozolomide when temozolomide was administered during the radiation phase at a lower dose of 50 mg/m² without maintenance (Strahlenther Onkol. 2005;181:372-7).

In RTOG 0525, 833 patients received concurrent radiation at 200 cGy in 30 fractions plus temozolomide 75 mg/m² daily, followed by 1:1 randomization to 6-12 cycles of standard temozolomide, starting at 150 mg/m² and escalating to 200 mg/m² if tolerated on days 1-5 of a 28-day cycle, or dose-dense temozolomide starting at 75 mg/m² and escalating to 100 mg/m² if tolerated on days 1-21 of a 28-day cycle.

Roughly one-fourth of patients were younger than 50 years old, more than half underwent total resection, and 45% had minor symptoms.

Grade 3-5 adverse events were significantly more common in the dose-dense arm, compared with the conventional arm (194 vs. 120; P less than .001), but they were mostly lymphopenia (107 vs. 51) and fatigue (33 vs. 12). No opportunistic infections occurred, Dr. Gilbert said.

The study was supported by Schering-Plough/Merck, the maker of temozolomide. Dr. Gilbert reported a consultant/advisory role with Genentech, and honoraria and research funding from Genentech and Merck. Several of his coauthors reported financial relationships with firms including Merck. Dr. Abrams reported that RTOG 0525 also receives funding from the National Cancer Institute, where he is employed. ☐