CNS/Brain Cancer

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

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

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

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

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

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

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

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

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Chinot disclosed receiving financial and nonfinancial support from Roche.

[email protected]

On Twitter @NikolaidesLaura

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

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

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

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

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

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

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

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

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Chinot disclosed receiving financial and nonfinancial support from Roche.

[email protected]

On Twitter @NikolaidesLaura

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

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

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

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

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

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

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

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

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Chinot disclosed receiving financial and nonfinancial support from Roche.

[email protected]

On Twitter @NikolaidesLaura

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BRUSSELS – In advanced-stage neuroblastoma patients with residual metastases in their bone marrow following two cycles of anti-GD2 immunotherapy, another cycle of this treatment is futile and only causes adverse events, based on a review of 343 stage IV patients treated at one U.S. center.

"Bone marrow minimal residual disease [MRD] measured after two cycles of immunotherapy was the strongest predictor of outcome, irrespective of disease status at the start of immunotherapy," Dr. Nai-Kong V. Cheung said at the Markers in Cancer meeting. "If a patient is positive for MRD after two cycles, don’t continue the treatment."

In the series of 343 patients aged 18 months or older with metastatic, stage IV neuroblastoma that he reviewed, all patients with detectable MRD after two cycles of immunotherapy with GD2 antibody eventually relapsed or died within the next 5 years. In contrast, roughly half of the patients who lacked MRD after the first two cycles of anti-GD2 therapy remained progression free and alive during up to 20 years of follow-up.

The full course of anti-GD2 treatment takes 2 years, has the potential to cause adverse effects, and is painful and expensive. "Why continue and subject patients to a treatment that won’t be beneficial?" Dr. Cheung asked during an interview. "We can use [MRD] as a marker to take patients off of a protocol that will not be useful to them and try a different treatment."

Immunotherapy with anti-GD2 is part of standard treatment for patients with advanced neuroblastoma.

Dr. Cheung, a pediatric oncologist and head of the neuroblastoma program at Memorial Sloan-Kettering Cancer Center in New York, and his associates used a four-marker genetic analysis to find evidence of residual, metastatic neuroblastoma cells in patients’ bone marrow. The four markers they used were:

• GD2 synthase, the gene for an enzyme that helps produce a ganglioside-abundant in neuroblastoma cells;

• PHOX2B, the gene for a transcription factor that promotes nerve cell growth and maturation;

• CCND1, the gene for cyclin D1 protein, an oncogene; and

• ISL 1, the gene for islet 1, a transcription factor involved in cell growth.

The database included 169 patients treated during first remission, 69 treated during second or later remission, and 105 with primary refractory disease. The researchers used the four-test genetic panel to screen for MRD in bone marrow specimens taken from these patients after the first two rounds of anti-GD2 treatment with or without granulocyte-macrophage colony-stimulating factor in a series of four treatment protocols. A patient was considered positive for MRD if at least one of the genetic markers was positive for the presence of neuroblastoma cells in the bone marrow.

In a multivariate analysis, patients negative for MRD had about a fourfold increased rate of progression-free survival and about a threefold increased rate of overall survival, compared with patients positive for MRD; both differences were statistically significant.

Dr. Cheung said that the four-gene panel his group used was developed through a project begun 15 years ago to look for the most discriminating gene signatures of metastatic neuroblastoma cells against the background of normal bone marrow cells, the metastatic destination for at least 90% of advanced neuroblastoma tumors. A similar approach could identify genetic tests for treatment response of other metastatic tumor types, he said.

The meeting was sponsored by the American Society of Clinical Oncology, the European Organisation for Research and Treatment of Cancer, and the National Cancer Institute. Dr. Cheung said that he is a coinventor on patents held by Memorial Sloan-Kettering Cancer Center.

[email protected]

On Twitter @mitchelzoler

BRUSSELS – In advanced-stage neuroblastoma patients with residual metastases in their bone marrow following two cycles of anti-GD2 immunotherapy, another cycle of this treatment is futile and only causes adverse events, based on a review of 343 stage IV patients treated at one U.S. center.

"Bone marrow minimal residual disease [MRD] measured after two cycles of immunotherapy was the strongest predictor of outcome, irrespective of disease status at the start of immunotherapy," Dr. Nai-Kong V. Cheung said at the Markers in Cancer meeting. "If a patient is positive for MRD after two cycles, don’t continue the treatment."

In the series of 343 patients aged 18 months or older with metastatic, stage IV neuroblastoma that he reviewed, all patients with detectable MRD after two cycles of immunotherapy with GD2 antibody eventually relapsed or died within the next 5 years. In contrast, roughly half of the patients who lacked MRD after the first two cycles of anti-GD2 therapy remained progression free and alive during up to 20 years of follow-up.

The full course of anti-GD2 treatment takes 2 years, has the potential to cause adverse effects, and is painful and expensive. "Why continue and subject patients to a treatment that won’t be beneficial?" Dr. Cheung asked during an interview. "We can use [MRD] as a marker to take patients off of a protocol that will not be useful to them and try a different treatment."

Immunotherapy with anti-GD2 is part of standard treatment for patients with advanced neuroblastoma.

Dr. Cheung, a pediatric oncologist and head of the neuroblastoma program at Memorial Sloan-Kettering Cancer Center in New York, and his associates used a four-marker genetic analysis to find evidence of residual, metastatic neuroblastoma cells in patients’ bone marrow. The four markers they used were:

• GD2 synthase, the gene for an enzyme that helps produce a ganglioside-abundant in neuroblastoma cells;

• PHOX2B, the gene for a transcription factor that promotes nerve cell growth and maturation;

• CCND1, the gene for cyclin D1 protein, an oncogene; and

• ISL 1, the gene for islet 1, a transcription factor involved in cell growth.

The database included 169 patients treated during first remission, 69 treated during second or later remission, and 105 with primary refractory disease. The researchers used the four-test genetic panel to screen for MRD in bone marrow specimens taken from these patients after the first two rounds of anti-GD2 treatment with or without granulocyte-macrophage colony-stimulating factor in a series of four treatment protocols. A patient was considered positive for MRD if at least one of the genetic markers was positive for the presence of neuroblastoma cells in the bone marrow.

In a multivariate analysis, patients negative for MRD had about a fourfold increased rate of progression-free survival and about a threefold increased rate of overall survival, compared with patients positive for MRD; both differences were statistically significant.

Dr. Cheung said that the four-gene panel his group used was developed through a project begun 15 years ago to look for the most discriminating gene signatures of metastatic neuroblastoma cells against the background of normal bone marrow cells, the metastatic destination for at least 90% of advanced neuroblastoma tumors. A similar approach could identify genetic tests for treatment response of other metastatic tumor types, he said.

The meeting was sponsored by the American Society of Clinical Oncology, the European Organisation for Research and Treatment of Cancer, and the National Cancer Institute. Dr. Cheung said that he is a coinventor on patents held by Memorial Sloan-Kettering Cancer Center.

[email protected]

On Twitter @mitchelzoler

BRUSSELS – In advanced-stage neuroblastoma patients with residual metastases in their bone marrow following two cycles of anti-GD2 immunotherapy, another cycle of this treatment is futile and only causes adverse events, based on a review of 343 stage IV patients treated at one U.S. center.

"Bone marrow minimal residual disease [MRD] measured after two cycles of immunotherapy was the strongest predictor of outcome, irrespective of disease status at the start of immunotherapy," Dr. Nai-Kong V. Cheung said at the Markers in Cancer meeting. "If a patient is positive for MRD after two cycles, don’t continue the treatment."

In the series of 343 patients aged 18 months or older with metastatic, stage IV neuroblastoma that he reviewed, all patients with detectable MRD after two cycles of immunotherapy with GD2 antibody eventually relapsed or died within the next 5 years. In contrast, roughly half of the patients who lacked MRD after the first two cycles of anti-GD2 therapy remained progression free and alive during up to 20 years of follow-up.

The full course of anti-GD2 treatment takes 2 years, has the potential to cause adverse effects, and is painful and expensive. "Why continue and subject patients to a treatment that won’t be beneficial?" Dr. Cheung asked during an interview. "We can use [MRD] as a marker to take patients off of a protocol that will not be useful to them and try a different treatment."

Immunotherapy with anti-GD2 is part of standard treatment for patients with advanced neuroblastoma.

Dr. Cheung, a pediatric oncologist and head of the neuroblastoma program at Memorial Sloan-Kettering Cancer Center in New York, and his associates used a four-marker genetic analysis to find evidence of residual, metastatic neuroblastoma cells in patients’ bone marrow. The four markers they used were:

• GD2 synthase, the gene for an enzyme that helps produce a ganglioside-abundant in neuroblastoma cells;

• PHOX2B, the gene for a transcription factor that promotes nerve cell growth and maturation;

• CCND1, the gene for cyclin D1 protein, an oncogene; and

• ISL 1, the gene for islet 1, a transcription factor involved in cell growth.

The database included 169 patients treated during first remission, 69 treated during second or later remission, and 105 with primary refractory disease. The researchers used the four-test genetic panel to screen for MRD in bone marrow specimens taken from these patients after the first two rounds of anti-GD2 treatment with or without granulocyte-macrophage colony-stimulating factor in a series of four treatment protocols. A patient was considered positive for MRD if at least one of the genetic markers was positive for the presence of neuroblastoma cells in the bone marrow.

In a multivariate analysis, patients negative for MRD had about a fourfold increased rate of progression-free survival and about a threefold increased rate of overall survival, compared with patients positive for MRD; both differences were statistically significant.

Dr. Cheung said that the four-gene panel his group used was developed through a project begun 15 years ago to look for the most discriminating gene signatures of metastatic neuroblastoma cells against the background of normal bone marrow cells, the metastatic destination for at least 90% of advanced neuroblastoma tumors. A similar approach could identify genetic tests for treatment response of other metastatic tumor types, he said.

The meeting was sponsored by the American Society of Clinical Oncology, the European Organisation for Research and Treatment of Cancer, and the National Cancer Institute. Dr. Cheung said that he is a coinventor on patents held by Memorial Sloan-Kettering Cancer Center.

[email protected]

On Twitter @mitchelzoler

AMSTERDAM – The investigational drug cilenglitide failed to improve overall or progression-free survival when added to standard treatment in patients with newly diagnosed glioblastoma.

Overall survival, the primary endpoint of the CENTRIC study, was 26.3 months in both study arms, with more events occurring in the cilenglitide arm than in the control arm (144 vs. 138; hazard ratio, 1.021; P = .86). "We could not identify any subgroup that actually had a benefit from the addition of cilenglitide," said study investigator Dr. Roger Stupp at the multidisciplinary European cancer congresses.

Sara Freeman/IMNG Medical Media

Progression-free survival, according to independent review, was also disappointing, at 10.6 months for the cilenglitide group and 7.9 months for the control group (HR, 0.918; P = .41), reported Dr. Stupp of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

These findings signal the end of the line for the drug’s development against this tumor, Dr. Stupp remarked in presenting the results of the large phase III study. "I’m not sure we are at the end of targeting integrins, but we have taken a blow with this strategy," he said.

CENTRIC was performed in 545 patients with newly diagnosed disease and a methylated promoter of the O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene.

The median age of enrolled patients was 58 years, with 23% aged 65 years or older. A total of 272 patients were randomized to receive cilenglitide in addition to standard chemoradiotherapy and 272 to chemoradiotherapy alone. Cilenglitide was given at an infused IV dose of 2,000 mg twice weekly. Standard chemoradiotherapy consisted of 75 mg/m² of temozolomide (TMZ), and radiotherapy consisted of a dose of 30 grays in 2-gray fractions, with maintenance TMZ (150-200 mg/m² for six cycles).

Another trial whose results were presented was the phase II CORE trial, which enrolled 265 patients with newly diagnosed glioblastoma and unmethylated MGMT. Patients were randomized into three groups: a control arm of standard chemotherapy of TMZ plus radiotherapy, and then maintenance TMZ (n = 89); a standard cilenglitide dosing arm, with patients receiving 2,000 mg twice a week in addition to chemoradiotherapy (n = 88); and an intensive dosing arm, with the dose of cilenglitide upped to 2,000 mg five times a week in addition to chemoradiotherapy (n = 88).

Contrary to the CENTRIC study results, the CORE study findings suggested there was a benefit of adding cilenglitide to standard therapy. Median overall survival was 13.4 months in the control arm, but 16.3 months in the standard cilenglitide dosing arm (hazard ratio, 0.69 vs. control). Median overall survival in the intensive treatment arm was 14.5 months (HR, 0.86 vs. control).

Sara Freeman/IMNG Medical Media

Investigator-assessed progression-free survival also suggested a benefit of adding cilenglitide.

"These findings are inconsistent with the larger, phase III CENTRIC clinical trial," said Dr. L. Burt Nabors of the University of Alabama at Birmingham, who presented the CORE findings. "This is a limited study. It was more exploratory in nature, with a sample size that was obviously smaller." He suggested that further investigations are required to look at possible biomarkers.

Commenting on the CENTRIC study, Dr. Michael Brada of University College Hospital, London, observed: "It’s been a bumpy year for randomized trials." Recent trials in glioblastoma have generally been disappointing, and the CENTRIC study results now add to the negative results.

Additional phase I/II trials are investigating the potential of cilenglitide in combination with radiotherapy and chemotherapy in patients with locally advanced non–small cell lung cancer (NCT01118676), and in combination with chemotherapy in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (NCT00705016).

The CENTRIC and CORE studies were sponsored by Merck. Dr. Stupp has received honoraria for consultancy work from Merck Serono, MSD-Merck, and Roche/Genentech. Dr. Nabors had no conflicts of interest to disclose. Dr. Brada has participated on advisory boards for Roche and Merck.

AMSTERDAM – The investigational drug cilenglitide failed to improve overall or progression-free survival when added to standard treatment in patients with newly diagnosed glioblastoma.

Overall survival, the primary endpoint of the CENTRIC study, was 26.3 months in both study arms, with more events occurring in the cilenglitide arm than in the control arm (144 vs. 138; hazard ratio, 1.021; P = .86). "We could not identify any subgroup that actually had a benefit from the addition of cilenglitide," said study investigator Dr. Roger Stupp at the multidisciplinary European cancer congresses.

Sara Freeman/IMNG Medical Media

Progression-free survival, according to independent review, was also disappointing, at 10.6 months for the cilenglitide group and 7.9 months for the control group (HR, 0.918; P = .41), reported Dr. Stupp of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

These findings signal the end of the line for the drug’s development against this tumor, Dr. Stupp remarked in presenting the results of the large phase III study. "I’m not sure we are at the end of targeting integrins, but we have taken a blow with this strategy," he said.

CENTRIC was performed in 545 patients with newly diagnosed disease and a methylated promoter of the O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene.

The median age of enrolled patients was 58 years, with 23% aged 65 years or older. A total of 272 patients were randomized to receive cilenglitide in addition to standard chemoradiotherapy and 272 to chemoradiotherapy alone. Cilenglitide was given at an infused IV dose of 2,000 mg twice weekly. Standard chemoradiotherapy consisted of 75 mg/m² of temozolomide (TMZ), and radiotherapy consisted of a dose of 30 grays in 2-gray fractions, with maintenance TMZ (150-200 mg/m² for six cycles).

Another trial whose results were presented was the phase II CORE trial, which enrolled 265 patients with newly diagnosed glioblastoma and unmethylated MGMT. Patients were randomized into three groups: a control arm of standard chemotherapy of TMZ plus radiotherapy, and then maintenance TMZ (n = 89); a standard cilenglitide dosing arm, with patients receiving 2,000 mg twice a week in addition to chemoradiotherapy (n = 88); and an intensive dosing arm, with the dose of cilenglitide upped to 2,000 mg five times a week in addition to chemoradiotherapy (n = 88).

Contrary to the CENTRIC study results, the CORE study findings suggested there was a benefit of adding cilenglitide to standard therapy. Median overall survival was 13.4 months in the control arm, but 16.3 months in the standard cilenglitide dosing arm (hazard ratio, 0.69 vs. control). Median overall survival in the intensive treatment arm was 14.5 months (HR, 0.86 vs. control).

Sara Freeman/IMNG Medical Media

Investigator-assessed progression-free survival also suggested a benefit of adding cilenglitide.

"These findings are inconsistent with the larger, phase III CENTRIC clinical trial," said Dr. L. Burt Nabors of the University of Alabama at Birmingham, who presented the CORE findings. "This is a limited study. It was more exploratory in nature, with a sample size that was obviously smaller." He suggested that further investigations are required to look at possible biomarkers.

Commenting on the CENTRIC study, Dr. Michael Brada of University College Hospital, London, observed: "It’s been a bumpy year for randomized trials." Recent trials in glioblastoma have generally been disappointing, and the CENTRIC study results now add to the negative results.

Additional phase I/II trials are investigating the potential of cilenglitide in combination with radiotherapy and chemotherapy in patients with locally advanced non–small cell lung cancer (NCT01118676), and in combination with chemotherapy in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (NCT00705016).

The CENTRIC and CORE studies were sponsored by Merck. Dr. Stupp has received honoraria for consultancy work from Merck Serono, MSD-Merck, and Roche/Genentech. Dr. Nabors had no conflicts of interest to disclose. Dr. Brada has participated on advisory boards for Roche and Merck.

AMSTERDAM – The investigational drug cilenglitide failed to improve overall or progression-free survival when added to standard treatment in patients with newly diagnosed glioblastoma.

Overall survival, the primary endpoint of the CENTRIC study, was 26.3 months in both study arms, with more events occurring in the cilenglitide arm than in the control arm (144 vs. 138; hazard ratio, 1.021; P = .86). "We could not identify any subgroup that actually had a benefit from the addition of cilenglitide," said study investigator Dr. Roger Stupp at the multidisciplinary European cancer congresses.

Sara Freeman/IMNG Medical Media

Progression-free survival, according to independent review, was also disappointing, at 10.6 months for the cilenglitide group and 7.9 months for the control group (HR, 0.918; P = .41), reported Dr. Stupp of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

These findings signal the end of the line for the drug’s development against this tumor, Dr. Stupp remarked in presenting the results of the large phase III study. "I’m not sure we are at the end of targeting integrins, but we have taken a blow with this strategy," he said.

CENTRIC was performed in 545 patients with newly diagnosed disease and a methylated promoter of the O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene.

The median age of enrolled patients was 58 years, with 23% aged 65 years or older. A total of 272 patients were randomized to receive cilenglitide in addition to standard chemoradiotherapy and 272 to chemoradiotherapy alone. Cilenglitide was given at an infused IV dose of 2,000 mg twice weekly. Standard chemoradiotherapy consisted of 75 mg/m² of temozolomide (TMZ), and radiotherapy consisted of a dose of 30 grays in 2-gray fractions, with maintenance TMZ (150-200 mg/m² for six cycles).

Another trial whose results were presented was the phase II CORE trial, which enrolled 265 patients with newly diagnosed glioblastoma and unmethylated MGMT. Patients were randomized into three groups: a control arm of standard chemotherapy of TMZ plus radiotherapy, and then maintenance TMZ (n = 89); a standard cilenglitide dosing arm, with patients receiving 2,000 mg twice a week in addition to chemoradiotherapy (n = 88); and an intensive dosing arm, with the dose of cilenglitide upped to 2,000 mg five times a week in addition to chemoradiotherapy (n = 88).

Contrary to the CENTRIC study results, the CORE study findings suggested there was a benefit of adding cilenglitide to standard therapy. Median overall survival was 13.4 months in the control arm, but 16.3 months in the standard cilenglitide dosing arm (hazard ratio, 0.69 vs. control). Median overall survival in the intensive treatment arm was 14.5 months (HR, 0.86 vs. control).

Sara Freeman/IMNG Medical Media

Investigator-assessed progression-free survival also suggested a benefit of adding cilenglitide.

"These findings are inconsistent with the larger, phase III CENTRIC clinical trial," said Dr. L. Burt Nabors of the University of Alabama at Birmingham, who presented the CORE findings. "This is a limited study. It was more exploratory in nature, with a sample size that was obviously smaller." He suggested that further investigations are required to look at possible biomarkers.

Commenting on the CENTRIC study, Dr. Michael Brada of University College Hospital, London, observed: "It’s been a bumpy year for randomized trials." Recent trials in glioblastoma have generally been disappointing, and the CENTRIC study results now add to the negative results.

Additional phase I/II trials are investigating the potential of cilenglitide in combination with radiotherapy and chemotherapy in patients with locally advanced non–small cell lung cancer (NCT01118676), and in combination with chemotherapy in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (NCT00705016).

The CENTRIC and CORE studies were sponsored by Merck. Dr. Stupp has received honoraria for consultancy work from Merck Serono, MSD-Merck, and Roche/Genentech. Dr. Nabors had no conflicts of interest to disclose. Dr. Brada has participated on advisory boards for Roche and Merck.

ATLANTA – Younger adults with one to three brain metastases survive longer when they are treated with stereotactic radiosurgery alone rather than whole-brain radiation therapy or a combination of both modalities, researchers reported at the annual meeting of the American Society for Radiation Oncology.

Among patients aged 35-50 years, stereotactic radiosurgery (SRS) alone was associated with hazard ratios (HR) for death ranging from 0.46 to 0.64, compared with an age-matched cohort treated with a combination of SRS and whole-brain radiation therapy (WBRT), based on a meta-analysis of data on 389 individual patients in three randomized clinical trials.

For local control, however, the data show a benefit for combined SRS and WBRT. For control of distant brain metastases, the data indicate a benefit for the combined therapies, but only among patients aged 55 years and older, reported Dr. Arjun Sahgal, associate professor of radiation oncology at the University of Toronto.

Courtesy ASTRO

"Our overall survival results favoring radiosurgery alone in younger patients may be explained by the lack of benefit of whole-brain radiation with respect to distant brain control in this cohort, while still exposing them to the harms of whole-brain radiation with respect to memory function and quality of life," he said.

Dr. Sahgal and his colleagues had previously published an aggregate meta-analysis showing that WBRT and SRS improved distant and local brain control but without overall survival benefit compared with SRS alone.

The current study looked at the raw, individual patient data from the three randomized controlled trials included in the original aggregate analysis. The trials included a 2006 study of 132 patients with an endpoint of brain tumor recurrence, a 2009 trial looking at the effect of SRS/WBRT on neurocognitive function in 58 patients, and a 2011 study examining the effect of adjuvant SRS on World Health Organization performance status scores.

The overall median time to local failure in the trials was 6.6 months for SRS alone, compared with 7.7 months for SRS/WBRT. Time to distant failure was also shorter with SRS alone, at a median of 4.7 vs. 7.7 months, respectively. Median time to death, however, was longer with SRS, at 10 vs. 8.2 months.

In a multivariate model for overall survival, the HR was 0.46 for patients at age 35 years, 0.52 at age 40, 0.58 at age 45, and 0.64 at age 50; all hazard ratios had significant confidence intervals. For patients aged 55 years and older, however, the HR for overall survival was not significant.

Patients with only one metastasis had a significantly lower risk of dying, compared with those who had two or three metastases (HR, 0.72).

The risk of local failure was significantly greater with SRS alone for patients aged 45-70.

The risk of new distant metastases was significant with SRS alone for patients aged 55 years and older, and was significantly lower for patients with one metastasis (HR, 0.63) vs. two or more metastases.

Salvage therapy was performed in 28% of patients who underwent SRS alone and 12% of those who received the combined therapies. Distant brain failures occurred in 54% of those in the SRS alone group, compared with 34% of those in the SRS/WBRT group.

Patients who underwent salvage therapy had significantly greater survival rates than those who did not, and this effect did not vary significantly by age, Dr. Sahgal reported.

The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.

ATLANTA – Younger adults with one to three brain metastases survive longer when they are treated with stereotactic radiosurgery alone rather than whole-brain radiation therapy or a combination of both modalities, researchers reported at the annual meeting of the American Society for Radiation Oncology.

Among patients aged 35-50 years, stereotactic radiosurgery (SRS) alone was associated with hazard ratios (HR) for death ranging from 0.46 to 0.64, compared with an age-matched cohort treated with a combination of SRS and whole-brain radiation therapy (WBRT), based on a meta-analysis of data on 389 individual patients in three randomized clinical trials.

For local control, however, the data show a benefit for combined SRS and WBRT. For control of distant brain metastases, the data indicate a benefit for the combined therapies, but only among patients aged 55 years and older, reported Dr. Arjun Sahgal, associate professor of radiation oncology at the University of Toronto.

Courtesy ASTRO

"Our overall survival results favoring radiosurgery alone in younger patients may be explained by the lack of benefit of whole-brain radiation with respect to distant brain control in this cohort, while still exposing them to the harms of whole-brain radiation with respect to memory function and quality of life," he said.

Dr. Sahgal and his colleagues had previously published an aggregate meta-analysis showing that WBRT and SRS improved distant and local brain control but without overall survival benefit compared with SRS alone.

The current study looked at the raw, individual patient data from the three randomized controlled trials included in the original aggregate analysis. The trials included a 2006 study of 132 patients with an endpoint of brain tumor recurrence, a 2009 trial looking at the effect of SRS/WBRT on neurocognitive function in 58 patients, and a 2011 study examining the effect of adjuvant SRS on World Health Organization performance status scores.

The overall median time to local failure in the trials was 6.6 months for SRS alone, compared with 7.7 months for SRS/WBRT. Time to distant failure was also shorter with SRS alone, at a median of 4.7 vs. 7.7 months, respectively. Median time to death, however, was longer with SRS, at 10 vs. 8.2 months.

In a multivariate model for overall survival, the HR was 0.46 for patients at age 35 years, 0.52 at age 40, 0.58 at age 45, and 0.64 at age 50; all hazard ratios had significant confidence intervals. For patients aged 55 years and older, however, the HR for overall survival was not significant.

Patients with only one metastasis had a significantly lower risk of dying, compared with those who had two or three metastases (HR, 0.72).

The risk of local failure was significantly greater with SRS alone for patients aged 45-70.

The risk of new distant metastases was significant with SRS alone for patients aged 55 years and older, and was significantly lower for patients with one metastasis (HR, 0.63) vs. two or more metastases.

Salvage therapy was performed in 28% of patients who underwent SRS alone and 12% of those who received the combined therapies. Distant brain failures occurred in 54% of those in the SRS alone group, compared with 34% of those in the SRS/WBRT group.

Patients who underwent salvage therapy had significantly greater survival rates than those who did not, and this effect did not vary significantly by age, Dr. Sahgal reported.

The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.

ATLANTA – Younger adults with one to three brain metastases survive longer when they are treated with stereotactic radiosurgery alone rather than whole-brain radiation therapy or a combination of both modalities, researchers reported at the annual meeting of the American Society for Radiation Oncology.

Among patients aged 35-50 years, stereotactic radiosurgery (SRS) alone was associated with hazard ratios (HR) for death ranging from 0.46 to 0.64, compared with an age-matched cohort treated with a combination of SRS and whole-brain radiation therapy (WBRT), based on a meta-analysis of data on 389 individual patients in three randomized clinical trials.

For local control, however, the data show a benefit for combined SRS and WBRT. For control of distant brain metastases, the data indicate a benefit for the combined therapies, but only among patients aged 55 years and older, reported Dr. Arjun Sahgal, associate professor of radiation oncology at the University of Toronto.

Courtesy ASTRO

"Our overall survival results favoring radiosurgery alone in younger patients may be explained by the lack of benefit of whole-brain radiation with respect to distant brain control in this cohort, while still exposing them to the harms of whole-brain radiation with respect to memory function and quality of life," he said.

Dr. Sahgal and his colleagues had previously published an aggregate meta-analysis showing that WBRT and SRS improved distant and local brain control but without overall survival benefit compared with SRS alone.

The current study looked at the raw, individual patient data from the three randomized controlled trials included in the original aggregate analysis. The trials included a 2006 study of 132 patients with an endpoint of brain tumor recurrence, a 2009 trial looking at the effect of SRS/WBRT on neurocognitive function in 58 patients, and a 2011 study examining the effect of adjuvant SRS on World Health Organization performance status scores.

The overall median time to local failure in the trials was 6.6 months for SRS alone, compared with 7.7 months for SRS/WBRT. Time to distant failure was also shorter with SRS alone, at a median of 4.7 vs. 7.7 months, respectively. Median time to death, however, was longer with SRS, at 10 vs. 8.2 months.

In a multivariate model for overall survival, the HR was 0.46 for patients at age 35 years, 0.52 at age 40, 0.58 at age 45, and 0.64 at age 50; all hazard ratios had significant confidence intervals. For patients aged 55 years and older, however, the HR for overall survival was not significant.

Patients with only one metastasis had a significantly lower risk of dying, compared with those who had two or three metastases (HR, 0.72).

The risk of local failure was significantly greater with SRS alone for patients aged 45-70.

The risk of new distant metastases was significant with SRS alone for patients aged 55 years and older, and was significantly lower for patients with one metastasis (HR, 0.63) vs. two or more metastases.

Salvage therapy was performed in 28% of patients who underwent SRS alone and 12% of those who received the combined therapies. Distant brain failures occurred in 54% of those in the SRS alone group, compared with 34% of those in the SRS/WBRT group.

Patients who underwent salvage therapy had significantly greater survival rates than those who did not, and this effect did not vary significantly by age, Dr. Sahgal reported.

The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.

ATLANTA – Patients with non–small cell lung cancer and fewer than four brain metastases treated with stereotactic radiosurgery had better overall survival than did similar patients treated with whole-brain irradiation in a nonrandomized observational study.

The study of 413 patients who were eligible for either treatment showed that the median overall survival was 9.0 months for those treated with stereotactic radiosurgery (SRS) alone, versus 3.9 months for those treated with whole-brain radiation therapy (WBRT) alone, reported Dr. Lia M. Halasz, assistant professor of radiation oncology at the University of Washington in Seattle.

The findings suggest the need for a randomized clinical trial comparing the two treatment strategies in patients with non–small cell lung cancer and up to three brain metastases, she said at the annual meeting of the American Society for Radiation Oncology.

"This observational data may better reflect real-world practice; however, the caveat is that all of these patients were treated at large NCCN [National Comprehensive Cancer Network] institutions, and may not reflect practices all across the United States," she said.

Dr. James B. Yu, a therapeutic radiologist and cancer outcomes researcher at Yale University, New Haven, Conn., commented that the study shows "at the very least, NCCN sites are doing a very good job at selecting patients for radiosurgery." Dr. Yu, the invited discussant, was not involved in the study.

There have been no randomized clinical trials directly comparing SRS alone vs. WBRT alone in patients with newly diagnosed brain metastases, and the optimal treatment for such patients is unknown, Dr. Halasz said. The investigators therefore undertook an observational study to determine whether one strategy had a therapeutic advantage over the other.

They identified 413 patients diagnosed with brain metastases without leptomeningeal disease from an NCCN longitudinal database from November 2006 through January 2010. The patients had all received radiation therapy with no neurosurgical resection within 60 days of diagnosis.

Of this group, 118 (29%) underwent SRS, 295 (71%) had WBRT; and 13 patients (3%) had both as initial treatment.

Patients with three or fewer metastases were significantly more likely to receive SRS than WBRT, whereas those with four or more metastases were more likely to receive WBRT (P less than .001). Other factors associated with choice of SRS were smaller metastases (P = .036) and one or no sites of extracranial disease, compared with two or more (P = .013).

The authors analyzed a subset of 197 patients with fewer than four brain metastases and all metastatic sites smaller than 4 cm, all of whom were eligible for either treatment, and 48% of whom underwent SRS alone. As noted before, the unadjusted overall survival in this group was 9.0 months for the SRS-treated patients, and 3.9 months for those treated with WBRT.

To compensate for patient-selection biases, the authors then performed a propensity score analysis in which they stratified patients by their propensity to receive radiosurgery. In this analysis, the estimated treatment effect of SRS on overall survival was a hazard ratio (HR) of 0.62 (P = .018). Factors significantly associated with overall survival included SRS vs. WBRT, number of brain metastases, extent of extracranial disease, institution, and year of treatment.

In an analysis using a standardized mortality-ratio weighing method, they found that the estimated treatment effect of SRS on overall survival was an HR of 0.67 (P = .007).

Additionally, the authors performed a sensitivity analysis of potential unmeasured confounders, assuming that patients who underwent WBRT were three times more likely to have a Karnofsky performance score less than 70, and that the HR for that poor performance status was 2.13, based on recursive partitioning analysis (RPA) status. In this analysis, the HR favoring SRS was 0.64 (P = .037).

Finally, they performed a companion analysis with breast cancer data, and found a similar HR in favor of SRS (HR, 0.59; P = .036)

The funding source for the study was not reported. Dr. Halasz and Dr. Yu reported having no conflicts of interest to disclose.

ATLANTA – Patients with non–small cell lung cancer and fewer than four brain metastases treated with stereotactic radiosurgery had better overall survival than did similar patients treated with whole-brain irradiation in a nonrandomized observational study.

The study of 413 patients who were eligible for either treatment showed that the median overall survival was 9.0 months for those treated with stereotactic radiosurgery (SRS) alone, versus 3.9 months for those treated with whole-brain radiation therapy (WBRT) alone, reported Dr. Lia M. Halasz, assistant professor of radiation oncology at the University of Washington in Seattle.

The findings suggest the need for a randomized clinical trial comparing the two treatment strategies in patients with non–small cell lung cancer and up to three brain metastases, she said at the annual meeting of the American Society for Radiation Oncology.

"This observational data may better reflect real-world practice; however, the caveat is that all of these patients were treated at large NCCN [National Comprehensive Cancer Network] institutions, and may not reflect practices all across the United States," she said.

Dr. James B. Yu, a therapeutic radiologist and cancer outcomes researcher at Yale University, New Haven, Conn., commented that the study shows "at the very least, NCCN sites are doing a very good job at selecting patients for radiosurgery." Dr. Yu, the invited discussant, was not involved in the study.

There have been no randomized clinical trials directly comparing SRS alone vs. WBRT alone in patients with newly diagnosed brain metastases, and the optimal treatment for such patients is unknown, Dr. Halasz said. The investigators therefore undertook an observational study to determine whether one strategy had a therapeutic advantage over the other.

They identified 413 patients diagnosed with brain metastases without leptomeningeal disease from an NCCN longitudinal database from November 2006 through January 2010. The patients had all received radiation therapy with no neurosurgical resection within 60 days of diagnosis.

Of this group, 118 (29%) underwent SRS, 295 (71%) had WBRT; and 13 patients (3%) had both as initial treatment.

Patients with three or fewer metastases were significantly more likely to receive SRS than WBRT, whereas those with four or more metastases were more likely to receive WBRT (P less than .001). Other factors associated with choice of SRS were smaller metastases (P = .036) and one or no sites of extracranial disease, compared with two or more (P = .013).

The authors analyzed a subset of 197 patients with fewer than four brain metastases and all metastatic sites smaller than 4 cm, all of whom were eligible for either treatment, and 48% of whom underwent SRS alone. As noted before, the unadjusted overall survival in this group was 9.0 months for the SRS-treated patients, and 3.9 months for those treated with WBRT.

To compensate for patient-selection biases, the authors then performed a propensity score analysis in which they stratified patients by their propensity to receive radiosurgery. In this analysis, the estimated treatment effect of SRS on overall survival was a hazard ratio (HR) of 0.62 (P = .018). Factors significantly associated with overall survival included SRS vs. WBRT, number of brain metastases, extent of extracranial disease, institution, and year of treatment.

In an analysis using a standardized mortality-ratio weighing method, they found that the estimated treatment effect of SRS on overall survival was an HR of 0.67 (P = .007).

Additionally, the authors performed a sensitivity analysis of potential unmeasured confounders, assuming that patients who underwent WBRT were three times more likely to have a Karnofsky performance score less than 70, and that the HR for that poor performance status was 2.13, based on recursive partitioning analysis (RPA) status. In this analysis, the HR favoring SRS was 0.64 (P = .037).

Finally, they performed a companion analysis with breast cancer data, and found a similar HR in favor of SRS (HR, 0.59; P = .036)

The funding source for the study was not reported. Dr. Halasz and Dr. Yu reported having no conflicts of interest to disclose.

ATLANTA – Patients with non–small cell lung cancer and fewer than four brain metastases treated with stereotactic radiosurgery had better overall survival than did similar patients treated with whole-brain irradiation in a nonrandomized observational study.

The study of 413 patients who were eligible for either treatment showed that the median overall survival was 9.0 months for those treated with stereotactic radiosurgery (SRS) alone, versus 3.9 months for those treated with whole-brain radiation therapy (WBRT) alone, reported Dr. Lia M. Halasz, assistant professor of radiation oncology at the University of Washington in Seattle.

The findings suggest the need for a randomized clinical trial comparing the two treatment strategies in patients with non–small cell lung cancer and up to three brain metastases, she said at the annual meeting of the American Society for Radiation Oncology.

"This observational data may better reflect real-world practice; however, the caveat is that all of these patients were treated at large NCCN [National Comprehensive Cancer Network] institutions, and may not reflect practices all across the United States," she said.

Dr. James B. Yu, a therapeutic radiologist and cancer outcomes researcher at Yale University, New Haven, Conn., commented that the study shows "at the very least, NCCN sites are doing a very good job at selecting patients for radiosurgery." Dr. Yu, the invited discussant, was not involved in the study.

There have been no randomized clinical trials directly comparing SRS alone vs. WBRT alone in patients with newly diagnosed brain metastases, and the optimal treatment for such patients is unknown, Dr. Halasz said. The investigators therefore undertook an observational study to determine whether one strategy had a therapeutic advantage over the other.

They identified 413 patients diagnosed with brain metastases without leptomeningeal disease from an NCCN longitudinal database from November 2006 through January 2010. The patients had all received radiation therapy with no neurosurgical resection within 60 days of diagnosis.

Of this group, 118 (29%) underwent SRS, 295 (71%) had WBRT; and 13 patients (3%) had both as initial treatment.

Patients with three or fewer metastases were significantly more likely to receive SRS than WBRT, whereas those with four or more metastases were more likely to receive WBRT (P less than .001). Other factors associated with choice of SRS were smaller metastases (P = .036) and one or no sites of extracranial disease, compared with two or more (P = .013).

The authors analyzed a subset of 197 patients with fewer than four brain metastases and all metastatic sites smaller than 4 cm, all of whom were eligible for either treatment, and 48% of whom underwent SRS alone. As noted before, the unadjusted overall survival in this group was 9.0 months for the SRS-treated patients, and 3.9 months for those treated with WBRT.

To compensate for patient-selection biases, the authors then performed a propensity score analysis in which they stratified patients by their propensity to receive radiosurgery. In this analysis, the estimated treatment effect of SRS on overall survival was a hazard ratio (HR) of 0.62 (P = .018). Factors significantly associated with overall survival included SRS vs. WBRT, number of brain metastases, extent of extracranial disease, institution, and year of treatment.

In an analysis using a standardized mortality-ratio weighing method, they found that the estimated treatment effect of SRS on overall survival was an HR of 0.67 (P = .007).

Additionally, the authors performed a sensitivity analysis of potential unmeasured confounders, assuming that patients who underwent WBRT were three times more likely to have a Karnofsky performance score less than 70, and that the HR for that poor performance status was 2.13, based on recursive partitioning analysis (RPA) status. In this analysis, the HR favoring SRS was 0.64 (P = .037).

Finally, they performed a companion analysis with breast cancer data, and found a similar HR in favor of SRS (HR, 0.59; P = .036)

The funding source for the study was not reported. Dr. Halasz and Dr. Yu reported having no conflicts of interest to disclose.

ATLANTA – Sparing the hippocampus during whole brain irradiation can pay off in memory preservation for months to come, according to Dr. Vinai Gondi.

Adults with brain metastases who underwent whole brain radiation therapy (WBRT) with a conformal technique designed to minimize radiation dose to the hippocampus had a significantly smaller mean decline in verbal memory 4 months after treatment than did historical controls, reported Dr. Gondi, codirector of the Cadence Health Brain Tumor Center in Chicago and a coprincipal investigator in the Radiation Therapy Oncology Group Trial 0933.

Neil Osterweil/IMNG Medical Media

"These phase II results are promising, and highlight the importance of the hippocampus as a radiosensitive structure central to memory toxicity," Dr. Gondi said in a briefing prior to his presentation in a plenary session of the American Society for Radiation Oncology.

The hippocampus has been shown to play host to neural stem cells that are constantly differentiating into new neurons throughout adult life, a process important for maintaining memory function, he noted.

Previous studies have shown that cranial irradiation with WBRT is associated with a 4- to 6-month decline in memory function, as measured by the Hopkins Verbal Learning Test (HVLT) total recall and delayed recall items.

By using intensity modulated radiation therapy (IMRT) to shape the beam and largely spare the pocket of neural stem cells in the dentate gyrus portion of the hippocampus, the investigators hoped to avoid the decrements in memory function seen with earlier, less discriminating WBRT techniques, he said.

They enrolled 113 adults with brain metastases from various primary malignancies and assigned them to receive hippocampal-avoiding WBRT of 30 Gy delivered in 10 fractions. Radiation oncologists participating in the trial were trained in the technique, which involves careful identification of hippocampal landmarks and titration of the dose to minimize exposure of the hippocampus in general, and the dentate gyrus in particular. Under the protocol, the total radiation dose to the entire volume of the hippocampus can be no more than 10 Gy, and no single point in the hippocampus can receive more than 17 Gy.

Controls were patients in an earlier phase III clinical trial who underwent WBRT without hippocampal avoidance.

At 4 months, 100 patients treated with the hippocampal-sparing technique who were available for analysis had a 7% decline in the primary endpoint – delayed recall scores from baseline – compared with 30% for historical controls (P = .0003).

Among the 29 patients for whom 6-month data were available, the mean relative decline from baseline in delayed recall was 2% and in immediate recall was 0.7%. In contrast, there was a 3% increase in total recall scores.

The risk of metastasis to the hippocampus was 4.5% during follow-up, Dr. Gondi said.

The Radiation Oncology Therapy Group is currently developing a phase III trial of prophylactic cranial radiation with or without hippocampal avoidance for patients with small cell lung cancer.

The study demonstrates the value of improving and incorporating into practice newer radiation delivery technologies such as IMRT, said Dr. Bruce G. Haffty, a radiation oncologist at the Cancer Institute of New Jersey in New Brunswick, and ASTRO president-elect.

"It’s nice to have that technology available, and it’s now nice to see that we can use that technology to [reduce] memory loss and improve quality of life for our patients undergoing whole brain radiation therapy," he said.

Dr. Haffty moderated the briefing, but was not involved in the study.

RTOG 0993 was supported by the National Cancer Institute. Dr. Gondi and Dr. Haffty reported having no relevant financial conflicts.

ATLANTA – Sparing the hippocampus during whole brain irradiation can pay off in memory preservation for months to come, according to Dr. Vinai Gondi.

Adults with brain metastases who underwent whole brain radiation therapy (WBRT) with a conformal technique designed to minimize radiation dose to the hippocampus had a significantly smaller mean decline in verbal memory 4 months after treatment than did historical controls, reported Dr. Gondi, codirector of the Cadence Health Brain Tumor Center in Chicago and a coprincipal investigator in the Radiation Therapy Oncology Group Trial 0933.

Neil Osterweil/IMNG Medical Media

"These phase II results are promising, and highlight the importance of the hippocampus as a radiosensitive structure central to memory toxicity," Dr. Gondi said in a briefing prior to his presentation in a plenary session of the American Society for Radiation Oncology.

The hippocampus has been shown to play host to neural stem cells that are constantly differentiating into new neurons throughout adult life, a process important for maintaining memory function, he noted.

Previous studies have shown that cranial irradiation with WBRT is associated with a 4- to 6-month decline in memory function, as measured by the Hopkins Verbal Learning Test (HVLT) total recall and delayed recall items.

By using intensity modulated radiation therapy (IMRT) to shape the beam and largely spare the pocket of neural stem cells in the dentate gyrus portion of the hippocampus, the investigators hoped to avoid the decrements in memory function seen with earlier, less discriminating WBRT techniques, he said.

They enrolled 113 adults with brain metastases from various primary malignancies and assigned them to receive hippocampal-avoiding WBRT of 30 Gy delivered in 10 fractions. Radiation oncologists participating in the trial were trained in the technique, which involves careful identification of hippocampal landmarks and titration of the dose to minimize exposure of the hippocampus in general, and the dentate gyrus in particular. Under the protocol, the total radiation dose to the entire volume of the hippocampus can be no more than 10 Gy, and no single point in the hippocampus can receive more than 17 Gy.

Controls were patients in an earlier phase III clinical trial who underwent WBRT without hippocampal avoidance.

At 4 months, 100 patients treated with the hippocampal-sparing technique who were available for analysis had a 7% decline in the primary endpoint – delayed recall scores from baseline – compared with 30% for historical controls (P = .0003).

Among the 29 patients for whom 6-month data were available, the mean relative decline from baseline in delayed recall was 2% and in immediate recall was 0.7%. In contrast, there was a 3% increase in total recall scores.

The risk of metastasis to the hippocampus was 4.5% during follow-up, Dr. Gondi said.

The Radiation Oncology Therapy Group is currently developing a phase III trial of prophylactic cranial radiation with or without hippocampal avoidance for patients with small cell lung cancer.

The study demonstrates the value of improving and incorporating into practice newer radiation delivery technologies such as IMRT, said Dr. Bruce G. Haffty, a radiation oncologist at the Cancer Institute of New Jersey in New Brunswick, and ASTRO president-elect.

"It’s nice to have that technology available, and it’s now nice to see that we can use that technology to [reduce] memory loss and improve quality of life for our patients undergoing whole brain radiation therapy," he said.

Dr. Haffty moderated the briefing, but was not involved in the study.

RTOG 0993 was supported by the National Cancer Institute. Dr. Gondi and Dr. Haffty reported having no relevant financial conflicts.

ATLANTA – Sparing the hippocampus during whole brain irradiation can pay off in memory preservation for months to come, according to Dr. Vinai Gondi.

Adults with brain metastases who underwent whole brain radiation therapy (WBRT) with a conformal technique designed to minimize radiation dose to the hippocampus had a significantly smaller mean decline in verbal memory 4 months after treatment than did historical controls, reported Dr. Gondi, codirector of the Cadence Health Brain Tumor Center in Chicago and a coprincipal investigator in the Radiation Therapy Oncology Group Trial 0933.

Neil Osterweil/IMNG Medical Media

"These phase II results are promising, and highlight the importance of the hippocampus as a radiosensitive structure central to memory toxicity," Dr. Gondi said in a briefing prior to his presentation in a plenary session of the American Society for Radiation Oncology.

The hippocampus has been shown to play host to neural stem cells that are constantly differentiating into new neurons throughout adult life, a process important for maintaining memory function, he noted.

Previous studies have shown that cranial irradiation with WBRT is associated with a 4- to 6-month decline in memory function, as measured by the Hopkins Verbal Learning Test (HVLT) total recall and delayed recall items.

By using intensity modulated radiation therapy (IMRT) to shape the beam and largely spare the pocket of neural stem cells in the dentate gyrus portion of the hippocampus, the investigators hoped to avoid the decrements in memory function seen with earlier, less discriminating WBRT techniques, he said.

They enrolled 113 adults with brain metastases from various primary malignancies and assigned them to receive hippocampal-avoiding WBRT of 30 Gy delivered in 10 fractions. Radiation oncologists participating in the trial were trained in the technique, which involves careful identification of hippocampal landmarks and titration of the dose to minimize exposure of the hippocampus in general, and the dentate gyrus in particular. Under the protocol, the total radiation dose to the entire volume of the hippocampus can be no more than 10 Gy, and no single point in the hippocampus can receive more than 17 Gy.

Controls were patients in an earlier phase III clinical trial who underwent WBRT without hippocampal avoidance.

At 4 months, 100 patients treated with the hippocampal-sparing technique who were available for analysis had a 7% decline in the primary endpoint – delayed recall scores from baseline – compared with 30% for historical controls (P = .0003).

Among the 29 patients for whom 6-month data were available, the mean relative decline from baseline in delayed recall was 2% and in immediate recall was 0.7%. In contrast, there was a 3% increase in total recall scores.

The risk of metastasis to the hippocampus was 4.5% during follow-up, Dr. Gondi said.

The Radiation Oncology Therapy Group is currently developing a phase III trial of prophylactic cranial radiation with or without hippocampal avoidance for patients with small cell lung cancer.

The study demonstrates the value of improving and incorporating into practice newer radiation delivery technologies such as IMRT, said Dr. Bruce G. Haffty, a radiation oncologist at the Cancer Institute of New Jersey in New Brunswick, and ASTRO president-elect.

"It’s nice to have that technology available, and it’s now nice to see that we can use that technology to [reduce] memory loss and improve quality of life for our patients undergoing whole brain radiation therapy," he said.

Dr. Haffty moderated the briefing, but was not involved in the study.

RTOG 0993 was supported by the National Cancer Institute. Dr. Gondi and Dr. Haffty reported having no relevant financial conflicts.

Reduced white matter and impaired neuropsychological function were seen 20-30 years later in childhood acute lymphoblastic leukemia and lymphoma survivors who received cranial radiotherapy.

Survivors treated with chemotherapy alone appeared to have milder impairments, with measures that were within one standard deviation of the measures seen in healthy controls, reported Ilse Schuitema of the University of Leiden and her associates.

They also found that a young age at the time of cranial radiotherapy and the radiation dosage were associated with poorer results on the MRI measure used to evaluate the white matter's microstructure. Decreases in this measure were associated with neuropsychological dysfunction. The study was published in the Sept. 20 issue of the Journal of Clinical Oncology (2013;31:3378-88).

The finding "warrants a recommendation to use CRT [cranial radiotherapy] only as a last resort," since chemotherapy is just as effective, based on survival and recurrence rates in patients with acute lymphoblastic leukemia (ALL). Further, indications of accelerated aging seen in survivors given cranial radiotherapy may support screening for early-onset dementia as well as recommending lifestyle modifications such as not smoking and getting regular physical exercise to slow the progress of dementia.

Ms. Schuitema of the department of clinical child and adolescent studies, faculty of social sciences at Leiden (the Netherlands) University, and her co-investigators, followed up with 93 survivors of ALL or lymphoma who had been treated between 1978 and 1990 with cranial radiotherapy or CNS-directed chemotherapy, and compared them with 49 healthy controls. The mean age of patients given chemotherapy only was 27 years and the mean age of those treated with radiotherapy was 31 years.

Testing included magnetic resonance diffusion tensor imaging and neuropsychological tests. Differences in fractional anisotropy on the MRI test were used to analyze white matter microstructure, and whole-brain, voxel-based analysis was performed.

Survivors treated with chemotherapy only had reductions in the MRI measure and neuropsychological performance, but the measures were no more than one standard deviation below the mean values of controls.

When compared with controls, survivors who had cranial radiotherapy had significant reductions in white matter integrity and lower neurocognitive function, with effects that included lower IQ, poorer visuomotor accuracy, and poorer work flow during sustained attention.

Further, there was a "steep decline," in the MRI measure within the frontal and parietal white matter, which "is a strong indication of accelerated aging" the researchers wrote. Some of the anatomical findings among those treated with CRT were similar to those found in people with Alzheimer's disease, suggesting that "the irradiated survivors could be at increased risk of developing early-onset dementia."

The study results highlight the importance of long-term follow-up of children who receive neurotoxic treatments and increase support "for the concept of accelerated aging after CRT implicates screening for early-onset dementia,"the researchers said.

The tests used in the study included the computerized Amsterdam Neuropsychological Tasks (ANT) program, used to assess executive functions, and the four subtest short-form of the Wechsler Adult Intelligence Scale Revised (WAIS-R III).

Ms. Schuitema's coauthors are from the University of Leiden; University Hospitals Leuven, Belgium; and Academic Medical Center, Amsterdam. The authors had no disclosures. The study was funded by grants, including one from the Dutch Cancer Society.

[email protected]

Reduced white matter and impaired neuropsychological function were seen 20-30 years later in childhood acute lymphoblastic leukemia and lymphoma survivors who received cranial radiotherapy.

Survivors treated with chemotherapy alone appeared to have milder impairments, with measures that were within one standard deviation of the measures seen in healthy controls, reported Ilse Schuitema of the University of Leiden and her associates.

They also found that a young age at the time of cranial radiotherapy and the radiation dosage were associated with poorer results on the MRI measure used to evaluate the white matter's microstructure. Decreases in this measure were associated with neuropsychological dysfunction. The study was published in the Sept. 20 issue of the Journal of Clinical Oncology (2013;31:3378-88).

The finding "warrants a recommendation to use CRT [cranial radiotherapy] only as a last resort," since chemotherapy is just as effective, based on survival and recurrence rates in patients with acute lymphoblastic leukemia (ALL). Further, indications of accelerated aging seen in survivors given cranial radiotherapy may support screening for early-onset dementia as well as recommending lifestyle modifications such as not smoking and getting regular physical exercise to slow the progress of dementia.

Ms. Schuitema of the department of clinical child and adolescent studies, faculty of social sciences at Leiden (the Netherlands) University, and her co-investigators, followed up with 93 survivors of ALL or lymphoma who had been treated between 1978 and 1990 with cranial radiotherapy or CNS-directed chemotherapy, and compared them with 49 healthy controls. The mean age of patients given chemotherapy only was 27 years and the mean age of those treated with radiotherapy was 31 years.

Testing included magnetic resonance diffusion tensor imaging and neuropsychological tests. Differences in fractional anisotropy on the MRI test were used to analyze white matter microstructure, and whole-brain, voxel-based analysis was performed.

Survivors treated with chemotherapy only had reductions in the MRI measure and neuropsychological performance, but the measures were no more than one standard deviation below the mean values of controls.

When compared with controls, survivors who had cranial radiotherapy had significant reductions in white matter integrity and lower neurocognitive function, with effects that included lower IQ, poorer visuomotor accuracy, and poorer work flow during sustained attention.

Further, there was a "steep decline," in the MRI measure within the frontal and parietal white matter, which "is a strong indication of accelerated aging" the researchers wrote. Some of the anatomical findings among those treated with CRT were similar to those found in people with Alzheimer's disease, suggesting that "the irradiated survivors could be at increased risk of developing early-onset dementia."

The study results highlight the importance of long-term follow-up of children who receive neurotoxic treatments and increase support "for the concept of accelerated aging after CRT implicates screening for early-onset dementia,"the researchers said.

The tests used in the study included the computerized Amsterdam Neuropsychological Tasks (ANT) program, used to assess executive functions, and the four subtest short-form of the Wechsler Adult Intelligence Scale Revised (WAIS-R III).

Ms. Schuitema's coauthors are from the University of Leiden; University Hospitals Leuven, Belgium; and Academic Medical Center, Amsterdam. The authors had no disclosures. The study was funded by grants, including one from the Dutch Cancer Society.

[email protected]

Reduced white matter and impaired neuropsychological function were seen 20-30 years later in childhood acute lymphoblastic leukemia and lymphoma survivors who received cranial radiotherapy.

Survivors treated with chemotherapy alone appeared to have milder impairments, with measures that were within one standard deviation of the measures seen in healthy controls, reported Ilse Schuitema of the University of Leiden and her associates.

They also found that a young age at the time of cranial radiotherapy and the radiation dosage were associated with poorer results on the MRI measure used to evaluate the white matter's microstructure. Decreases in this measure were associated with neuropsychological dysfunction. The study was published in the Sept. 20 issue of the Journal of Clinical Oncology (2013;31:3378-88).

The finding "warrants a recommendation to use CRT [cranial radiotherapy] only as a last resort," since chemotherapy is just as effective, based on survival and recurrence rates in patients with acute lymphoblastic leukemia (ALL). Further, indications of accelerated aging seen in survivors given cranial radiotherapy may support screening for early-onset dementia as well as recommending lifestyle modifications such as not smoking and getting regular physical exercise to slow the progress of dementia.

Ms. Schuitema of the department of clinical child and adolescent studies, faculty of social sciences at Leiden (the Netherlands) University, and her co-investigators, followed up with 93 survivors of ALL or lymphoma who had been treated between 1978 and 1990 with cranial radiotherapy or CNS-directed chemotherapy, and compared them with 49 healthy controls. The mean age of patients given chemotherapy only was 27 years and the mean age of those treated with radiotherapy was 31 years.

Testing included magnetic resonance diffusion tensor imaging and neuropsychological tests. Differences in fractional anisotropy on the MRI test were used to analyze white matter microstructure, and whole-brain, voxel-based analysis was performed.

Survivors treated with chemotherapy only had reductions in the MRI measure and neuropsychological performance, but the measures were no more than one standard deviation below the mean values of controls.

When compared with controls, survivors who had cranial radiotherapy had significant reductions in white matter integrity and lower neurocognitive function, with effects that included lower IQ, poorer visuomotor accuracy, and poorer work flow during sustained attention.

Further, there was a "steep decline," in the MRI measure within the frontal and parietal white matter, which "is a strong indication of accelerated aging" the researchers wrote. Some of the anatomical findings among those treated with CRT were similar to those found in people with Alzheimer's disease, suggesting that "the irradiated survivors could be at increased risk of developing early-onset dementia."

The study results highlight the importance of long-term follow-up of children who receive neurotoxic treatments and increase support "for the concept of accelerated aging after CRT implicates screening for early-onset dementia,"the researchers said.

The tests used in the study included the computerized Amsterdam Neuropsychological Tasks (ANT) program, used to assess executive functions, and the four subtest short-form of the Wechsler Adult Intelligence Scale Revised (WAIS-R III).

Ms. Schuitema's coauthors are from the University of Leiden; University Hospitals Leuven, Belgium; and Academic Medical Center, Amsterdam. The authors had no disclosures. The study was funded by grants, including one from the Dutch Cancer Society.

[email protected]

A plasma protein involved in tumor oxidation and reduction reactions was useful for detecting and excluding lung cancer in more than three quarters of clinical samples evaluated in a large prospective study.

Isocitrate dehydrogenase 1 (IDH1) measurement was associated with a sensitivity of 77.1% and specificity of 76.2% in a training set of samples (n = 712), and 82.9% sensitivity and 76.6% specificity in a second validation or test set (n = 710).

Sensitivity and specificity were generally improved when the protein’s detection was considered in addition to other known or proposed non–small-cell lung cancer (NSCLC) biomarkers, with sensitivities of 75.8% and 86.3% in the training and test sets, respectively, and specificities of 89.6% and 70.7%.

"Some existing NSCLC biomarkers, such as CEA [carcinoembryonic antigen] and Cyfra21-1 [cytokeratin fragment 21-1], have been used in clinical practice, whereas others, such as CA125 [cancer antigen 125], have been recommended for further validation," Dr. Nan Sun and associates reported in the latest issue of Clinical Cancer Research.

"These biomarkers have low sensitivity, ranging from 50% to 60%, with specificities of approximately 90%," said the researchers, of the department of thoracic surgical oncology at the Cancer Institute and Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences in Beijing.

Previous research by the team had shown IDH1 levels were elevated in tumor samples taken from patients with NSCLC (Mol. Cell. Proteomics 2012;11:M111). Their present investigation (Clin. Cancer. Res. 2013; 19: 5136-45) therefore aimed to see if the protein’s measurement could aid in the diagnosis of lung cancer, differentiating between those who did and those who did not have malignant disease.

For their investigation, the team obtained 1,422 blood samples from 943 patients with previously untreated NSCLC and 479 healthy individuals who were seen for routine examinations between 2007 and 2011 at their institution.

The blood samples from the lung cancer patients were taken 3 days prior to their undergoing surgery and IDH1 levels were immediately determined by enzyme-linked immunosorbent assay, while CEA, Cyfra21-1, and CA125 levels were measured with an Elecys immunoassay analyzer.

Median levels of IDH1 were 2.39 U/L higher than those of healthy controls for squamous cell carcinoma cases (n = 489) cases and 1.96 U/L higher for adenocarcinoma cases (n = 454). Additionally, median plasma levels of IDH1 were higher in patients with adenocarcinomas than in those with squamous cell carcinomas (P = .012)

"We have identified IDH1 as an effective plasma biomarker with high sensitivity and specificity in the diagnosis of NSCLC, especially lung adenocarcinoma," senior study investigator Dr. Jie He said in a press release issued by the American Association for Cancer Research. "Based on the present data, IDH1 can be used to detect stage 1 lung cancer,"

The protein might also detect precancerous lesions, but further studies are required to test that hypothesis, said Dr. He. IDH1 might be a good target for NSCLC treatment as it "may be involved in the development of lung cancer."

A multicenter clinical trial is planned to further validate the diagnostic utility of IDH1.

Research funding was provided by the National High Technology Research and Development Program of China, the International Science and Technology Corporation and Exchange Project, the National Natural Science Foundation of China, the Doctoral Fund of Ministry of Education of China, and the Government Health Care Research Foundation for Senior Officials. The authors had no conflicts of interest to disclose.

A plasma protein involved in tumor oxidation and reduction reactions was useful for detecting and excluding lung cancer in more than three quarters of clinical samples evaluated in a large prospective study.

Isocitrate dehydrogenase 1 (IDH1) measurement was associated with a sensitivity of 77.1% and specificity of 76.2% in a training set of samples (n = 712), and 82.9% sensitivity and 76.6% specificity in a second validation or test set (n = 710).

Sensitivity and specificity were generally improved when the protein’s detection was considered in addition to other known or proposed non–small-cell lung cancer (NSCLC) biomarkers, with sensitivities of 75.8% and 86.3% in the training and test sets, respectively, and specificities of 89.6% and 70.7%.

"Some existing NSCLC biomarkers, such as CEA [carcinoembryonic antigen] and Cyfra21-1 [cytokeratin fragment 21-1], have been used in clinical practice, whereas others, such as CA125 [cancer antigen 125], have been recommended for further validation," Dr. Nan Sun and associates reported in the latest issue of Clinical Cancer Research.

"These biomarkers have low sensitivity, ranging from 50% to 60%, with specificities of approximately 90%," said the researchers, of the department of thoracic surgical oncology at the Cancer Institute and Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences in Beijing.

Previous research by the team had shown IDH1 levels were elevated in tumor samples taken from patients with NSCLC (Mol. Cell. Proteomics 2012;11:M111). Their present investigation (Clin. Cancer. Res. 2013; 19: 5136-45) therefore aimed to see if the protein’s measurement could aid in the diagnosis of lung cancer, differentiating between those who did and those who did not have malignant disease.

For their investigation, the team obtained 1,422 blood samples from 943 patients with previously untreated NSCLC and 479 healthy individuals who were seen for routine examinations between 2007 and 2011 at their institution.

The blood samples from the lung cancer patients were taken 3 days prior to their undergoing surgery and IDH1 levels were immediately determined by enzyme-linked immunosorbent assay, while CEA, Cyfra21-1, and CA125 levels were measured with an Elecys immunoassay analyzer.

Median levels of IDH1 were 2.39 U/L higher than those of healthy controls for squamous cell carcinoma cases (n = 489) cases and 1.96 U/L higher for adenocarcinoma cases (n = 454). Additionally, median plasma levels of IDH1 were higher in patients with adenocarcinomas than in those with squamous cell carcinomas (P = .012)

"We have identified IDH1 as an effective plasma biomarker with high sensitivity and specificity in the diagnosis of NSCLC, especially lung adenocarcinoma," senior study investigator Dr. Jie He said in a press release issued by the American Association for Cancer Research. "Based on the present data, IDH1 can be used to detect stage 1 lung cancer,"

The protein might also detect precancerous lesions, but further studies are required to test that hypothesis, said Dr. He. IDH1 might be a good target for NSCLC treatment as it "may be involved in the development of lung cancer."

A multicenter clinical trial is planned to further validate the diagnostic utility of IDH1.

Research funding was provided by the National High Technology Research and Development Program of China, the International Science and Technology Corporation and Exchange Project, the National Natural Science Foundation of China, the Doctoral Fund of Ministry of Education of China, and the Government Health Care Research Foundation for Senior Officials. The authors had no conflicts of interest to disclose.

A plasma protein involved in tumor oxidation and reduction reactions was useful for detecting and excluding lung cancer in more than three quarters of clinical samples evaluated in a large prospective study.

Isocitrate dehydrogenase 1 (IDH1) measurement was associated with a sensitivity of 77.1% and specificity of 76.2% in a training set of samples (n = 712), and 82.9% sensitivity and 76.6% specificity in a second validation or test set (n = 710).

Sensitivity and specificity were generally improved when the protein’s detection was considered in addition to other known or proposed non–small-cell lung cancer (NSCLC) biomarkers, with sensitivities of 75.8% and 86.3% in the training and test sets, respectively, and specificities of 89.6% and 70.7%.

"Some existing NSCLC biomarkers, such as CEA [carcinoembryonic antigen] and Cyfra21-1 [cytokeratin fragment 21-1], have been used in clinical practice, whereas others, such as CA125 [cancer antigen 125], have been recommended for further validation," Dr. Nan Sun and associates reported in the latest issue of Clinical Cancer Research.

"These biomarkers have low sensitivity, ranging from 50% to 60%, with specificities of approximately 90%," said the researchers, of the department of thoracic surgical oncology at the Cancer Institute and Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences in Beijing.

Previous research by the team had shown IDH1 levels were elevated in tumor samples taken from patients with NSCLC (Mol. Cell. Proteomics 2012;11:M111). Their present investigation (Clin. Cancer. Res. 2013; 19: 5136-45) therefore aimed to see if the protein’s measurement could aid in the diagnosis of lung cancer, differentiating between those who did and those who did not have malignant disease.

For their investigation, the team obtained 1,422 blood samples from 943 patients with previously untreated NSCLC and 479 healthy individuals who were seen for routine examinations between 2007 and 2011 at their institution.

The blood samples from the lung cancer patients were taken 3 days prior to their undergoing surgery and IDH1 levels were immediately determined by enzyme-linked immunosorbent assay, while CEA, Cyfra21-1, and CA125 levels were measured with an Elecys immunoassay analyzer.

Median levels of IDH1 were 2.39 U/L higher than those of healthy controls for squamous cell carcinoma cases (n = 489) cases and 1.96 U/L higher for adenocarcinoma cases (n = 454). Additionally, median plasma levels of IDH1 were higher in patients with adenocarcinomas than in those with squamous cell carcinomas (P = .012)

"We have identified IDH1 as an effective plasma biomarker with high sensitivity and specificity in the diagnosis of NSCLC, especially lung adenocarcinoma," senior study investigator Dr. Jie He said in a press release issued by the American Association for Cancer Research. "Based on the present data, IDH1 can be used to detect stage 1 lung cancer,"

The protein might also detect precancerous lesions, but further studies are required to test that hypothesis, said Dr. He. IDH1 might be a good target for NSCLC treatment as it "may be involved in the development of lung cancer."

A multicenter clinical trial is planned to further validate the diagnostic utility of IDH1.

Research funding was provided by the National High Technology Research and Development Program of China, the International Science and Technology Corporation and Exchange Project, the National Natural Science Foundation of China, the Doctoral Fund of Ministry of Education of China, and the Government Health Care Research Foundation for Senior Officials. The authors had no conflicts of interest to disclose.

CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.

At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.

Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.

Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.

The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.

The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).

A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m² per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m² per day for days 1-5 of each 28-day cycle for a total of 12 cycles.

The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.

The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.

In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).

In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.

Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.

In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."

In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.

The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.

CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.

At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.

Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.

Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.

The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.

The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).

A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m² per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m² per day for days 1-5 of each 28-day cycle for a total of 12 cycles.

The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.

The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.

In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).

In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.

Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.

In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."

In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.

The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.

CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.

At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.

Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.

Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.

The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.

The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).

A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m² per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m² per day for days 1-5 of each 28-day cycle for a total of 12 cycles.

The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.

The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.

In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).

In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.

Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.

In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."

In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.

The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.