Neuro-oncology

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Major Finding: Global HRQOL scores at 9 months were significantly worse in patients who received WBRT than in those who underwent observation alone (52.2 vs. 63.2, respectively).

Data Source: Randomized trial of 359 patients who underwent either observation or adjuvant whole-brain radiotherapy after surgical or radiosurgical resection of between 1 and 3 brain metastases.

Disclosures: The European Organization for Research and Treatment of Cancer sponsored the trial. Dr. Soffietti did not offer disclosure information.

MONTREAL – Adjuvant whole-brain radiotherapy following surgical or radiosurgical resection of brain metastases provided no survival benefit and modestly reduced health-related quality of life when compared with close MRI observation alone in a randomized study of 359 patients.

The worsening of health-related quality of life with whole-brain radiotherapy (WBRT) was slight and transient, first author Dr. Riccardo Soffietti said at the annual meeting of the Society for Neuro-Oncology. He noted that few scores “reached clinical or statistical significance, and most scores that differed significantly at the first time-point had a tendency to recover over time.”

The study was a secondary analysis of a phase III study in which patients were randomized to receive WBRT (180 patients) or undergo observation with MRI every 3 months (179) after undergoing surgery or radiosurgery for one to three brain metastases. The primary results of the study were published online in the Journal of Clinical Oncology (doi:10.1200/JCO.2010.30.1655).

For the primary outcome of overall survival at 1 year, there was no difference in between the WBRT (median of 10.9 months) and observation groups (10.7 months). Both groups also had a similar degree of functional independence.

There was a modest increase in progression-free survival in the WBRT group “probably due to their significant reduction in intracranial progression,” said Dr. Soffietti, professor of neuro-oncology at the University of Torino (Italy).

Intracranial progression causing death occurred in 28% of the WBRT group, compared with 44% of the observation group.

For the secondary end point of health-related quality of life (HRQOL), there was low patient compliance in completing the brain-specific questionnaires QLQ-C30 and BN-20. Only 315 (88%) of the participants completed baseline assessments, while many fewer completed 6-month (51%) or 1-year assessments (45%).

Among the patients for whom all assessments were available, Dr. Soffietti and his colleagues noted “a statistically significant and clinically relevant difference between the two arms at 9 months favoring patients who did not receive whole-brain radiation therapy.” However, the difference in global HRQOL scores at that time (52.2 in the WBRT group and 63.2 in the observation group) was only transitory and was not maintained by the 1-year mark.

Major Finding: Global HRQOL scores at 9 months were significantly worse in patients who received WBRT than in those who underwent observation alone (52.2 vs. 63.2, respectively).

Data Source: Randomized trial of 359 patients who underwent either observation or adjuvant whole-brain radiotherapy after surgical or radiosurgical resection of between 1 and 3 brain metastases.

Disclosures: The European Organization for Research and Treatment of Cancer sponsored the trial. Dr. Soffietti did not offer disclosure information.

MONTREAL – Adjuvant whole-brain radiotherapy following surgical or radiosurgical resection of brain metastases provided no survival benefit and modestly reduced health-related quality of life when compared with close MRI observation alone in a randomized study of 359 patients.

The worsening of health-related quality of life with whole-brain radiotherapy (WBRT) was slight and transient, first author Dr. Riccardo Soffietti said at the annual meeting of the Society for Neuro-Oncology. He noted that few scores “reached clinical or statistical significance, and most scores that differed significantly at the first time-point had a tendency to recover over time.”

The study was a secondary analysis of a phase III study in which patients were randomized to receive WBRT (180 patients) or undergo observation with MRI every 3 months (179) after undergoing surgery or radiosurgery for one to three brain metastases. The primary results of the study were published online in the Journal of Clinical Oncology (doi:10.1200/JCO.2010.30.1655).

For the primary outcome of overall survival at 1 year, there was no difference in between the WBRT (median of 10.9 months) and observation groups (10.7 months). Both groups also had a similar degree of functional independence.

There was a modest increase in progression-free survival in the WBRT group “probably due to their significant reduction in intracranial progression,” said Dr. Soffietti, professor of neuro-oncology at the University of Torino (Italy).

Intracranial progression causing death occurred in 28% of the WBRT group, compared with 44% of the observation group.

For the secondary end point of health-related quality of life (HRQOL), there was low patient compliance in completing the brain-specific questionnaires QLQ-C30 and BN-20. Only 315 (88%) of the participants completed baseline assessments, while many fewer completed 6-month (51%) or 1-year assessments (45%).

Among the patients for whom all assessments were available, Dr. Soffietti and his colleagues noted “a statistically significant and clinically relevant difference between the two arms at 9 months favoring patients who did not receive whole-brain radiation therapy.” However, the difference in global HRQOL scores at that time (52.2 in the WBRT group and 63.2 in the observation group) was only transitory and was not maintained by the 1-year mark.

Major Finding: Global HRQOL scores at 9 months were significantly worse in patients who received WBRT than in those who underwent observation alone (52.2 vs. 63.2, respectively).

Data Source: Randomized trial of 359 patients who underwent either observation or adjuvant whole-brain radiotherapy after surgical or radiosurgical resection of between 1 and 3 brain metastases.

Disclosures: The European Organization for Research and Treatment of Cancer sponsored the trial. Dr. Soffietti did not offer disclosure information.

MONTREAL – Adjuvant whole-brain radiotherapy following surgical or radiosurgical resection of brain metastases provided no survival benefit and modestly reduced health-related quality of life when compared with close MRI observation alone in a randomized study of 359 patients.

The worsening of health-related quality of life with whole-brain radiotherapy (WBRT) was slight and transient, first author Dr. Riccardo Soffietti said at the annual meeting of the Society for Neuro-Oncology. He noted that few scores “reached clinical or statistical significance, and most scores that differed significantly at the first time-point had a tendency to recover over time.”

The study was a secondary analysis of a phase III study in which patients were randomized to receive WBRT (180 patients) or undergo observation with MRI every 3 months (179) after undergoing surgery or radiosurgery for one to three brain metastases. The primary results of the study were published online in the Journal of Clinical Oncology (doi:10.1200/JCO.2010.30.1655).

For the primary outcome of overall survival at 1 year, there was no difference in between the WBRT (median of 10.9 months) and observation groups (10.7 months). Both groups also had a similar degree of functional independence.

There was a modest increase in progression-free survival in the WBRT group “probably due to their significant reduction in intracranial progression,” said Dr. Soffietti, professor of neuro-oncology at the University of Torino (Italy).

Intracranial progression causing death occurred in 28% of the WBRT group, compared with 44% of the observation group.

For the secondary end point of health-related quality of life (HRQOL), there was low patient compliance in completing the brain-specific questionnaires QLQ-C30 and BN-20. Only 315 (88%) of the participants completed baseline assessments, while many fewer completed 6-month (51%) or 1-year assessments (45%).

Among the patients for whom all assessments were available, Dr. Soffietti and his colleagues noted “a statistically significant and clinically relevant difference between the two arms at 9 months favoring patients who did not receive whole-brain radiation therapy.” However, the difference in global HRQOL scores at that time (52.2 in the WBRT group and 63.2 in the observation group) was only transitory and was not maintained by the 1-year mark.

Major Finding: Two phase II studies of vatalanib and sunitinib showed 6-month progression-free survival rates of 57% and 36%, respectively.

Data Source: Two cohorts of 25 and 36 patients with recurrent grade II and III meningiomas.

Disclosures: Pfizer funded the study on its drug, sunitinib, and Novartis funded the study on its investigational drug, vatalanib. The investigators did not provide financial disclosure information at the meeting and did not respond to inquiries about disclosures.

MONTREAL – The tyrosine kinase inhibitors vatalanib and sunitinib may offer alternative approaches to treating patients with recurrent, high-grade meningioma who have failed surgery and radiation therapy, according to two separate phase II studies.

Both drugs significantly improved survival compared with what is generally expected in this patient population, most of whom had grade II or III tumors. Progression-free survival at 6 months occurred in 57% of 25 patients with meningioma who received the investigational drug vatalanib in one study, and in 36% of 36 patients who received sunitinib in another study. Both drugs are inhibitors of receptors for vascular endothelial growth factor and platelet-derived growth factor.

Sunitinib is marketed under the brand name Sutent and has been approved by the Food and Drug Administration for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumor after disease progression on – or intolerance to – imatinib mesylate (Gleevec).

Progression-free survival (PFS) for patients with recurrent grade II and III tumors is usually considered to occur in fewer than 5%, said Dr. Jeffrey Raizer, who presented the vatalanib study at the meeting.

“For recurrence of meningioma, treatment options are limited once patients have failed surgery and radiation, and chemotherapies have been very limited to date,” said Dr. Raizer, director of medical neuro-oncology at the cancer center of Northwestern University and Northwestern Memorial Hospital, both in Chicago.

Despite the encouraging findings of the two studies, a lack of information on the natural history of these tumors makes it difficult to interpret the studies, said Dr. Michael Vogelbaum, who chaired the session in which the studies were presented.

“While the studies suggest there may be some promise, we don't really know what to expect from that mix of grade II and III tumors on their own,” Dr. Vogelbaum said in an interview. He is chair of neuro-oncology at the Cleveland Clinic Neurological Institute.

Dr. Fred Barker of the department of neurosurgery at Massachusetts General Hospital, Boston, echoed Dr. Vogelbaum's comments. “The results are interesting, but we don't know exactly what the natural history would be without treatment, so whether there's a benefit to giving these drugs will require further study.”

In Dr. Raizer's Pfizer-sponsored study of vatalanib in meningioma patients, the median PFS was 5.9 months, and the median overall survival was 22.3 months. Of the 25 patients in the study, 22 had grade II and III tumors and 14 were men. The PFS at 6 months was comparable between patients with grade II (39%) or grade III disease only (43%).

Dosing of vatalanib began at 250 mg twice daily and rose by 250 mg/day every 7 days until it reached 500 mg twice daily.

For 21 patients with available imaging data, tumors partially responded to treatment in 1, remained stable in 15, and progressed in 5 patients.

The most common adverse events were fatigue, rash, and elevated transaminases.

The sunitinib study, sponsored by Novartis, included 36 patients (median age, 62 years) with recurrent grade II and III meningiomas who had exhausted all surgical and radiation options. The patients had a median of five recurrences.

The primary end point of PFS at 6 months was 36% and the median PFS was 5.1 months. The overall survival rate is not known, as only eight patients have died, reported Dr. Thomas Kaley, codirector of the neuro-oncology fellowship program at Memorial Sloan-Kettering Cancer Center in New York.

Imaging was available for 34 patients and showed stable disease in 26, a partial response in 1, and progressive disease in 7 patients, he said. The dose of sunitinib was 50 mg/day orally on a 4-week-on, 2-week-off cycle.

Major Finding: Two phase II studies of vatalanib and sunitinib showed 6-month progression-free survival rates of 57% and 36%, respectively.

Data Source: Two cohorts of 25 and 36 patients with recurrent grade II and III meningiomas.

Disclosures: Pfizer funded the study on its drug, sunitinib, and Novartis funded the study on its investigational drug, vatalanib. The investigators did not provide financial disclosure information at the meeting and did not respond to inquiries about disclosures.

MONTREAL – The tyrosine kinase inhibitors vatalanib and sunitinib may offer alternative approaches to treating patients with recurrent, high-grade meningioma who have failed surgery and radiation therapy, according to two separate phase II studies.

Both drugs significantly improved survival compared with what is generally expected in this patient population, most of whom had grade II or III tumors. Progression-free survival at 6 months occurred in 57% of 25 patients with meningioma who received the investigational drug vatalanib in one study, and in 36% of 36 patients who received sunitinib in another study. Both drugs are inhibitors of receptors for vascular endothelial growth factor and platelet-derived growth factor.

Sunitinib is marketed under the brand name Sutent and has been approved by the Food and Drug Administration for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumor after disease progression on – or intolerance to – imatinib mesylate (Gleevec).

Progression-free survival (PFS) for patients with recurrent grade II and III tumors is usually considered to occur in fewer than 5%, said Dr. Jeffrey Raizer, who presented the vatalanib study at the meeting.

“For recurrence of meningioma, treatment options are limited once patients have failed surgery and radiation, and chemotherapies have been very limited to date,” said Dr. Raizer, director of medical neuro-oncology at the cancer center of Northwestern University and Northwestern Memorial Hospital, both in Chicago.

Despite the encouraging findings of the two studies, a lack of information on the natural history of these tumors makes it difficult to interpret the studies, said Dr. Michael Vogelbaum, who chaired the session in which the studies were presented.

“While the studies suggest there may be some promise, we don't really know what to expect from that mix of grade II and III tumors on their own,” Dr. Vogelbaum said in an interview. He is chair of neuro-oncology at the Cleveland Clinic Neurological Institute.

Dr. Fred Barker of the department of neurosurgery at Massachusetts General Hospital, Boston, echoed Dr. Vogelbaum's comments. “The results are interesting, but we don't know exactly what the natural history would be without treatment, so whether there's a benefit to giving these drugs will require further study.”

In Dr. Raizer's Pfizer-sponsored study of vatalanib in meningioma patients, the median PFS was 5.9 months, and the median overall survival was 22.3 months. Of the 25 patients in the study, 22 had grade II and III tumors and 14 were men. The PFS at 6 months was comparable between patients with grade II (39%) or grade III disease only (43%).

Dosing of vatalanib began at 250 mg twice daily and rose by 250 mg/day every 7 days until it reached 500 mg twice daily.

For 21 patients with available imaging data, tumors partially responded to treatment in 1, remained stable in 15, and progressed in 5 patients.

The most common adverse events were fatigue, rash, and elevated transaminases.

The sunitinib study, sponsored by Novartis, included 36 patients (median age, 62 years) with recurrent grade II and III meningiomas who had exhausted all surgical and radiation options. The patients had a median of five recurrences.

The primary end point of PFS at 6 months was 36% and the median PFS was 5.1 months. The overall survival rate is not known, as only eight patients have died, reported Dr. Thomas Kaley, codirector of the neuro-oncology fellowship program at Memorial Sloan-Kettering Cancer Center in New York.

Imaging was available for 34 patients and showed stable disease in 26, a partial response in 1, and progressive disease in 7 patients, he said. The dose of sunitinib was 50 mg/day orally on a 4-week-on, 2-week-off cycle.

Major Finding: Two phase II studies of vatalanib and sunitinib showed 6-month progression-free survival rates of 57% and 36%, respectively.

Data Source: Two cohorts of 25 and 36 patients with recurrent grade II and III meningiomas.

Disclosures: Pfizer funded the study on its drug, sunitinib, and Novartis funded the study on its investigational drug, vatalanib. The investigators did not provide financial disclosure information at the meeting and did not respond to inquiries about disclosures.

MONTREAL – The tyrosine kinase inhibitors vatalanib and sunitinib may offer alternative approaches to treating patients with recurrent, high-grade meningioma who have failed surgery and radiation therapy, according to two separate phase II studies.

Both drugs significantly improved survival compared with what is generally expected in this patient population, most of whom had grade II or III tumors. Progression-free survival at 6 months occurred in 57% of 25 patients with meningioma who received the investigational drug vatalanib in one study, and in 36% of 36 patients who received sunitinib in another study. Both drugs are inhibitors of receptors for vascular endothelial growth factor and platelet-derived growth factor.

Sunitinib is marketed under the brand name Sutent and has been approved by the Food and Drug Administration for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumor after disease progression on – or intolerance to – imatinib mesylate (Gleevec).

Progression-free survival (PFS) for patients with recurrent grade II and III tumors is usually considered to occur in fewer than 5%, said Dr. Jeffrey Raizer, who presented the vatalanib study at the meeting.

“For recurrence of meningioma, treatment options are limited once patients have failed surgery and radiation, and chemotherapies have been very limited to date,” said Dr. Raizer, director of medical neuro-oncology at the cancer center of Northwestern University and Northwestern Memorial Hospital, both in Chicago.

Despite the encouraging findings of the two studies, a lack of information on the natural history of these tumors makes it difficult to interpret the studies, said Dr. Michael Vogelbaum, who chaired the session in which the studies were presented.

“While the studies suggest there may be some promise, we don't really know what to expect from that mix of grade II and III tumors on their own,” Dr. Vogelbaum said in an interview. He is chair of neuro-oncology at the Cleveland Clinic Neurological Institute.

Dr. Fred Barker of the department of neurosurgery at Massachusetts General Hospital, Boston, echoed Dr. Vogelbaum's comments. “The results are interesting, but we don't know exactly what the natural history would be without treatment, so whether there's a benefit to giving these drugs will require further study.”

In Dr. Raizer's Pfizer-sponsored study of vatalanib in meningioma patients, the median PFS was 5.9 months, and the median overall survival was 22.3 months. Of the 25 patients in the study, 22 had grade II and III tumors and 14 were men. The PFS at 6 months was comparable between patients with grade II (39%) or grade III disease only (43%).

Dosing of vatalanib began at 250 mg twice daily and rose by 250 mg/day every 7 days until it reached 500 mg twice daily.

For 21 patients with available imaging data, tumors partially responded to treatment in 1, remained stable in 15, and progressed in 5 patients.

The most common adverse events were fatigue, rash, and elevated transaminases.

The sunitinib study, sponsored by Novartis, included 36 patients (median age, 62 years) with recurrent grade II and III meningiomas who had exhausted all surgical and radiation options. The patients had a median of five recurrences.

The primary end point of PFS at 6 months was 36% and the median PFS was 5.1 months. The overall survival rate is not known, as only eight patients have died, reported Dr. Thomas Kaley, codirector of the neuro-oncology fellowship program at Memorial Sloan-Kettering Cancer Center in New York.

Imaging was available for 34 patients and showed stable disease in 26, a partial response in 1, and progressive disease in 7 patients, he said. The dose of sunitinib was 50 mg/day orally on a 4-week-on, 2-week-off cycle.

Major Finding: More than half of patients with a median Karnofsky performance score of 60 improved their score by at least 10 points.

Data Source: A group of 70 elderly, poor-performance patients, treated with postsurgical temozolomide for newly diagnosed glioblastoma.

Disclosures: Dr. Pérez-Larraya reported having no relevant financial disclosures.

MONTREAL – Elderly patients with newly diagnosed glioblastoma and poor Karnofsky performance scores can benefit from postsurgical chemotherapy with temozolomide, based on the results of a single-arm study in 70 patients.

Most patients were able to withstand treatment-related toxicity, and survival rates and performance status appeared to improve with treatment, Dr. Jamie Gállego Pérez-Larraya said at the meetingo

Median overall survival, the primary end point, reached 25 weeks, with a 6-month overall survival rate of 44.3% and a 12-month rate of 11.4%, said Dr. Pérez-Larraya of Hôpital Pitié-Salpêtrière in Paris. Median progression-free survival, a secondary end point, was 16 weeks, with a 6-month rate of 30%. “These data compare favorably to the 17-week median survival reported in elderly patients with glioblastoma and good performance treated only with palliative care,” he said.

The trial from ANOCEF (Association des Neuro-Oncologues d'Expression Française) enrolled 70 patients aged 70 and up (median age, 77 years), with newly diagnosed and histologically confirmed glioblastoma, a median Karnofsky performance score of 60, and no previous radiotherapy or chemotherapy for the brain tumor. Most (92%) had undergone biopsy of their tumor; five patients had received a partial resection, and one had a complete resection.

Temozolomide chemotherapy started at 150 mg/m

Quality of life (QOL) and cognitive function outcomes were measured by EORTC (European Organisation for Research and Treatment of Cancer) questionnaires (QLQ-C30 and QLQ-BN20), and the Mini-Mental State Examination. The stuidy showed significant improvements on the global QOL scale and most functioning domains, with no decline in any domain, he said.

A third of the cohort improved in Karnofsky performance scores by at least 10 points, and 26% achieved a score of 70 or greater. “This is clinically significant because it means they became capable of self-care,” he noted.

Treatment with temozolomide was “generally well tolerated,” Dr. Pérez-Larraya reported. Twelve patients, (17%) had grade 3 or 4 thrombocytopenia or neutropenia, but these toxicities did not lead to dose delays or dose reductions. All of the cohort had died by the time of presentation – 87% as a result of disease progression, and 13% from other causes, with no deaths due to toxicity.

“Until a few years ago the treatment of these patients received little attention mainly because of their poor expected survival, but also because of the fear of treatment-related toxicity,” said Dr. Pérez-Larraya. Now patients with good performance scores can be treated with postsurgical radiotherapy, which has been shown to prolong survival from 17 weeks to 29 weeks without causing deterioration in QOL or cognitive function (N. Engl. J. Med. 2007;356(1527-35). But management of patients with poor scores has never been studied, he said. “Radiotherapy requires many trips to the hospital, and increasing fatigue makes this difficult for these severely impaired patients with such a short expected survival,” he said.

The results suggest that temozolomide in elderly patients with glioblastoma and poor performance scores “has an acceptable safety profile; is associated with an improvement in functional status in one-third of cases, and quality of life before progression; and seems to increase survival as compared to supportive care alone,” Dr. Pérez-Larraya concluded.

View on the News

Therapeutic Nihilism Unnecessary

This study clearly shows the acceptable toxicity and benefit of temozolomide in the treatment of elderly patients with low performance scores who received this drug after surgery for newly diagnosed glioblastoma. Temozolomide appeared to improve both survival rates and performance.

The findings highlight the need to get rid of the nihilistic approach toward this population, all too frequently relegated to hospice without any attempt at therapy. The toxicity was small and the benefits were real, a lesson all physicians caring for the elderly with glioblastoma should remember.

DR. HENRY S. FRIEDMAN is a professor of neuro-oncology and deputy director of the Preston Robert Tisch Brain Tumor Center at Duke University, Durham, N.C. He also serves as an advisor to Genentech.

Vitals

Major Finding: More than half of patients with a median Karnofsky performance score of 60 improved their score by at least 10 points.

Data Source: A group of 70 elderly, poor-performance patients, treated with postsurgical temozolomide for newly diagnosed glioblastoma.

Disclosures: Dr. Pérez-Larraya reported having no relevant financial disclosures.

MONTREAL – Elderly patients with newly diagnosed glioblastoma and poor Karnofsky performance scores can benefit from postsurgical chemotherapy with temozolomide, based on the results of a single-arm study in 70 patients.

Most patients were able to withstand treatment-related toxicity, and survival rates and performance status appeared to improve with treatment, Dr. Jamie Gállego Pérez-Larraya said at the meetingo

Median overall survival, the primary end point, reached 25 weeks, with a 6-month overall survival rate of 44.3% and a 12-month rate of 11.4%, said Dr. Pérez-Larraya of Hôpital Pitié-Salpêtrière in Paris. Median progression-free survival, a secondary end point, was 16 weeks, with a 6-month rate of 30%. “These data compare favorably to the 17-week median survival reported in elderly patients with glioblastoma and good performance treated only with palliative care,” he said.

The trial from ANOCEF (Association des Neuro-Oncologues d'Expression Française) enrolled 70 patients aged 70 and up (median age, 77 years), with newly diagnosed and histologically confirmed glioblastoma, a median Karnofsky performance score of 60, and no previous radiotherapy or chemotherapy for the brain tumor. Most (92%) had undergone biopsy of their tumor; five patients had received a partial resection, and one had a complete resection.

Temozolomide chemotherapy started at 150 mg/m

Quality of life (QOL) and cognitive function outcomes were measured by EORTC (European Organisation for Research and Treatment of Cancer) questionnaires (QLQ-C30 and QLQ-BN20), and the Mini-Mental State Examination. The stuidy showed significant improvements on the global QOL scale and most functioning domains, with no decline in any domain, he said.

A third of the cohort improved in Karnofsky performance scores by at least 10 points, and 26% achieved a score of 70 or greater. “This is clinically significant because it means they became capable of self-care,” he noted.

Treatment with temozolomide was “generally well tolerated,” Dr. Pérez-Larraya reported. Twelve patients, (17%) had grade 3 or 4 thrombocytopenia or neutropenia, but these toxicities did not lead to dose delays or dose reductions. All of the cohort had died by the time of presentation – 87% as a result of disease progression, and 13% from other causes, with no deaths due to toxicity.

“Until a few years ago the treatment of these patients received little attention mainly because of their poor expected survival, but also because of the fear of treatment-related toxicity,” said Dr. Pérez-Larraya. Now patients with good performance scores can be treated with postsurgical radiotherapy, which has been shown to prolong survival from 17 weeks to 29 weeks without causing deterioration in QOL or cognitive function (N. Engl. J. Med. 2007;356(1527-35). But management of patients with poor scores has never been studied, he said. “Radiotherapy requires many trips to the hospital, and increasing fatigue makes this difficult for these severely impaired patients with such a short expected survival,” he said.

The results suggest that temozolomide in elderly patients with glioblastoma and poor performance scores “has an acceptable safety profile; is associated with an improvement in functional status in one-third of cases, and quality of life before progression; and seems to increase survival as compared to supportive care alone,” Dr. Pérez-Larraya concluded.

View on the News

Therapeutic Nihilism Unnecessary

This study clearly shows the acceptable toxicity and benefit of temozolomide in the treatment of elderly patients with low performance scores who received this drug after surgery for newly diagnosed glioblastoma. Temozolomide appeared to improve both survival rates and performance.

The findings highlight the need to get rid of the nihilistic approach toward this population, all too frequently relegated to hospice without any attempt at therapy. The toxicity was small and the benefits were real, a lesson all physicians caring for the elderly with glioblastoma should remember.

DR. HENRY S. FRIEDMAN is a professor of neuro-oncology and deputy director of the Preston Robert Tisch Brain Tumor Center at Duke University, Durham, N.C. He also serves as an advisor to Genentech.

Vitals

Major Finding: More than half of patients with a median Karnofsky performance score of 60 improved their score by at least 10 points.

Data Source: A group of 70 elderly, poor-performance patients, treated with postsurgical temozolomide for newly diagnosed glioblastoma.

Disclosures: Dr. Pérez-Larraya reported having no relevant financial disclosures.

MONTREAL – Elderly patients with newly diagnosed glioblastoma and poor Karnofsky performance scores can benefit from postsurgical chemotherapy with temozolomide, based on the results of a single-arm study in 70 patients.

Most patients were able to withstand treatment-related toxicity, and survival rates and performance status appeared to improve with treatment, Dr. Jamie Gállego Pérez-Larraya said at the meetingo

Median overall survival, the primary end point, reached 25 weeks, with a 6-month overall survival rate of 44.3% and a 12-month rate of 11.4%, said Dr. Pérez-Larraya of Hôpital Pitié-Salpêtrière in Paris. Median progression-free survival, a secondary end point, was 16 weeks, with a 6-month rate of 30%. “These data compare favorably to the 17-week median survival reported in elderly patients with glioblastoma and good performance treated only with palliative care,” he said.

The trial from ANOCEF (Association des Neuro-Oncologues d'Expression Française) enrolled 70 patients aged 70 and up (median age, 77 years), with newly diagnosed and histologically confirmed glioblastoma, a median Karnofsky performance score of 60, and no previous radiotherapy or chemotherapy for the brain tumor. Most (92%) had undergone biopsy of their tumor; five patients had received a partial resection, and one had a complete resection.

Temozolomide chemotherapy started at 150 mg/m

Quality of life (QOL) and cognitive function outcomes were measured by EORTC (European Organisation for Research and Treatment of Cancer) questionnaires (QLQ-C30 and QLQ-BN20), and the Mini-Mental State Examination. The stuidy showed significant improvements on the global QOL scale and most functioning domains, with no decline in any domain, he said.

A third of the cohort improved in Karnofsky performance scores by at least 10 points, and 26% achieved a score of 70 or greater. “This is clinically significant because it means they became capable of self-care,” he noted.

Treatment with temozolomide was “generally well tolerated,” Dr. Pérez-Larraya reported. Twelve patients, (17%) had grade 3 or 4 thrombocytopenia or neutropenia, but these toxicities did not lead to dose delays or dose reductions. All of the cohort had died by the time of presentation – 87% as a result of disease progression, and 13% from other causes, with no deaths due to toxicity.

“Until a few years ago the treatment of these patients received little attention mainly because of their poor expected survival, but also because of the fear of treatment-related toxicity,” said Dr. Pérez-Larraya. Now patients with good performance scores can be treated with postsurgical radiotherapy, which has been shown to prolong survival from 17 weeks to 29 weeks without causing deterioration in QOL or cognitive function (N. Engl. J. Med. 2007;356(1527-35). But management of patients with poor scores has never been studied, he said. “Radiotherapy requires many trips to the hospital, and increasing fatigue makes this difficult for these severely impaired patients with such a short expected survival,” he said.

The results suggest that temozolomide in elderly patients with glioblastoma and poor performance scores “has an acceptable safety profile; is associated with an improvement in functional status in one-third of cases, and quality of life before progression; and seems to increase survival as compared to supportive care alone,” Dr. Pérez-Larraya concluded.

View on the News

Therapeutic Nihilism Unnecessary

This study clearly shows the acceptable toxicity and benefit of temozolomide in the treatment of elderly patients with low performance scores who received this drug after surgery for newly diagnosed glioblastoma. Temozolomide appeared to improve both survival rates and performance.

The findings highlight the need to get rid of the nihilistic approach toward this population, all too frequently relegated to hospice without any attempt at therapy. The toxicity was small and the benefits were real, a lesson all physicians caring for the elderly with glioblastoma should remember.

DR. HENRY S. FRIEDMAN is a professor of neuro-oncology and deputy director of the Preston Robert Tisch Brain Tumor Center at Duke University, Durham, N.C. He also serves as an advisor to Genentech.

Vitals

Major Finding: 1-year overall survival in a subgroup of patients was significantly higher among those treated with NovoTTF-100A than it was in those who received chemotherapy (35.2% vs. 20.8%).

Data Source: Post hoc subgroup analysis of 237 patients with recurrent glioblastoma.

Disclosures: Dr. Zvi Ram disclosed that he is a consultant for NovoCure, which sponsored the trial and manufactures the device. Dr. Brandes said that she had no relevant financial disclosures.

MONTREAL – An investigational treatment for recurrent glioblastoma that delivers alternating electric fields through scalp electrodes has shown signs of improved survival in a post hoc analysis of results in particular subgroups of patients in a phase III trial.

Quality of life outcomes also favored patients who used the device, known as NovoTTF-100A, compared with those who received chemotherapy.

To date, reports about the device have elicited both antagonistic and enthusiastic reaction from oncologists, with “neither the enthusiasts nor the antagonists having significant basis for either kind of acute reaction,” Dr. Zvi Ram said in an interview after presenting the subgroup analyses at the meetingo “I think it is exciting that we're getting something completely new – a different, noninvasive modality with no side effects. I think we should be exhilarated.”

The device delivers low-amplitude “tumor treatment fields” of 100–300 kHz that have been shown in vitro to slow and reverse tumor cell proliferation by inhibiting mitosis, according to NovoCure Ltd., the manufacturer of the device and sponsor of the trial.

The portable device weighs about 6 pounds and connects to a battery pack. It is designed to be worn almost constantly, with a target of at least 20 hours of use each day.

In a phase III clinical trial presented earlier this year at the American Society of Clinical Oncology, an intent-to-treat analysis comparing NovoTTF vs. best-available chemotherapy found no statistical difference in 1-year overall survival (OS) among 237 recurrent glioblastoma patients randomized to either treatment.

However, a per-protocol analysis (which included only those patients who wore the device for at least 70% of the recommended time during the first month) showed a statistically significant benefit to NovoTTF in 1-year survival, compared with chemotherapy (29.5% vs. 19.1%, respectively; hazard ratio, 0.64; P = .01).

In the new post hoc analysis, a subgroup of 110 patients with a “good prognosis” (aged younger than 60 years, and with a Karnofsky performance status score greater than 80%) showed a “more robust” survival benefit than that seen in the overall intent-to-treat analysis, he said.

In this subgroup, patients treated with NovoTTF had a median survival of 9.2 months, vs. 6.6 months in those treated with chemotherapy (P less than .01). However, in the overall intent-to-treat group, median survival was 6.6 months and 6.0 months, respectively, he explained. Moreover, the 1-year OS in this subgroup was significantly higher in the NovoTTF group than in the chemotherapy group (35.2% vs. 20.8%, respectively; P less than .01), whereas the difference was nonsignificant in the larger analysis (23.6% vs. 20.7%).

Another subgroup analysis looked at patients who had previously failed treatment with bevacizumab (about 20% of the entire cohort). Both an intent-to-treat analysis and a per-protocol analysis showed significant OS advantages to NovoTTF, said Dr. Ram, chair of neurosurgery at Tel Aviv (Israel) Medical Center.

The median OS in 44 patients in the intent-to-treat group was 4 months with NovoTTF vs. 3.1 months with chemotherapy (HR, 0.43; P less than .02). NovoTTF also gave a significantly better median OS among 29 patients in the per-protocol analysis for this subgroup (6.3 months vs. 3.3 months; HR, 0.21; P = .02).

“You don't see this anywhere,” he said. “There's no drug in the world that could produce such response in patients who had already failed” bevacizumab.

The investigators also analyzed a surgery-naive group. “You know these are going to be poor responders, almost identical to [those with] bevacizumab failure,” Dr. Ram commented.

In this group of 38 patients, an intent-to-treat analysis showed that overall survival was 9.8 months with NovoTTF vs. 5.5 months with chemotherapy.

Patients also reported significantly better quality of life with NovoTTF than with chemotherapy. On the Quality of Life Symptom Scale, NovoTTF patients scored −34 and −35 on constipation and diarrhea, compared with scores of +77 and +50 for the chemotherapy group. Nausea and vomiting scores were 15 for the NovoTTF group and 61 for the chemotherapy group, and pain scores were −1 for the NovoTTF group and +63 for the chemotherapy group.

A quality of life analysis using the EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 instrument showed scores of 14 vs. −7 in favor of NovoTTF for cognitive functioning, and scores of 7 vs. 1 in favor of NovoTTF for emotional functioning.

“We do this to all our patients. We intoxicate them,” Dr. Ram said. “So even if NovoTTF did not extend survival, if it was equivalent to chemotherapy [for survival], it may still improve quality of life.”

Dr. Ram did not know the median length of time that the NovoTTF cohort wore the device, but an earlier phase II study followed some patients up to 59 months. He noted that “70% are still alive; that's unheard of.”

“There were concerns that patients might have more headaches or seizures, but there were none,” he added.

In the current study, the rate of adverse events related to the central nervous system was similar (66% for NovoTTF and 67% for chemotherapy). Seizures occurred in 15% of the NovoTTF group and 12% of the chemotherapy group, and headaches occurred in 18% and 13%, respectively.

“It's very interesting and exciting, even if we do not yet have enough definitive data,” commented Dr. Alba B. Brandes, moderator of the session and the chair of medical oncology at Azienda USL, a group of nine hospitals in and around Bologna, Italy.

The investigators have been criticized for repackaging their nonsignificant intent-to-treat results into per-protocol results that show significance, she said. “An intention-to-treat population and per-protocol population are two different things, and from a statistical point of view, it is sometimes difficult for the oncologic community to accept.” Despite those reservations, she said that the per-protocol observations should not be dismissed, because when they are analyzed in this way the results are highly significant.

Dr. Ram acknowledged that per-protocol analysis is unconventional, but “there is no precedent for this kind of therapy and I think we may need to redesign the way we assess results in the future. We cannot use the same guidelines and definitions we were traditionally using.”

Major Finding: 1-year overall survival in a subgroup of patients was significantly higher among those treated with NovoTTF-100A than it was in those who received chemotherapy (35.2% vs. 20.8%).

Data Source: Post hoc subgroup analysis of 237 patients with recurrent glioblastoma.

Disclosures: Dr. Zvi Ram disclosed that he is a consultant for NovoCure, which sponsored the trial and manufactures the device. Dr. Brandes said that she had no relevant financial disclosures.

MONTREAL – An investigational treatment for recurrent glioblastoma that delivers alternating electric fields through scalp electrodes has shown signs of improved survival in a post hoc analysis of results in particular subgroups of patients in a phase III trial.

Quality of life outcomes also favored patients who used the device, known as NovoTTF-100A, compared with those who received chemotherapy.

To date, reports about the device have elicited both antagonistic and enthusiastic reaction from oncologists, with “neither the enthusiasts nor the antagonists having significant basis for either kind of acute reaction,” Dr. Zvi Ram said in an interview after presenting the subgroup analyses at the meetingo “I think it is exciting that we're getting something completely new – a different, noninvasive modality with no side effects. I think we should be exhilarated.”

The device delivers low-amplitude “tumor treatment fields” of 100–300 kHz that have been shown in vitro to slow and reverse tumor cell proliferation by inhibiting mitosis, according to NovoCure Ltd., the manufacturer of the device and sponsor of the trial.

The portable device weighs about 6 pounds and connects to a battery pack. It is designed to be worn almost constantly, with a target of at least 20 hours of use each day.

In a phase III clinical trial presented earlier this year at the American Society of Clinical Oncology, an intent-to-treat analysis comparing NovoTTF vs. best-available chemotherapy found no statistical difference in 1-year overall survival (OS) among 237 recurrent glioblastoma patients randomized to either treatment.

However, a per-protocol analysis (which included only those patients who wore the device for at least 70% of the recommended time during the first month) showed a statistically significant benefit to NovoTTF in 1-year survival, compared with chemotherapy (29.5% vs. 19.1%, respectively; hazard ratio, 0.64; P = .01).

In the new post hoc analysis, a subgroup of 110 patients with a “good prognosis” (aged younger than 60 years, and with a Karnofsky performance status score greater than 80%) showed a “more robust” survival benefit than that seen in the overall intent-to-treat analysis, he said.

In this subgroup, patients treated with NovoTTF had a median survival of 9.2 months, vs. 6.6 months in those treated with chemotherapy (P less than .01). However, in the overall intent-to-treat group, median survival was 6.6 months and 6.0 months, respectively, he explained. Moreover, the 1-year OS in this subgroup was significantly higher in the NovoTTF group than in the chemotherapy group (35.2% vs. 20.8%, respectively; P less than .01), whereas the difference was nonsignificant in the larger analysis (23.6% vs. 20.7%).

Another subgroup analysis looked at patients who had previously failed treatment with bevacizumab (about 20% of the entire cohort). Both an intent-to-treat analysis and a per-protocol analysis showed significant OS advantages to NovoTTF, said Dr. Ram, chair of neurosurgery at Tel Aviv (Israel) Medical Center.

The median OS in 44 patients in the intent-to-treat group was 4 months with NovoTTF vs. 3.1 months with chemotherapy (HR, 0.43; P less than .02). NovoTTF also gave a significantly better median OS among 29 patients in the per-protocol analysis for this subgroup (6.3 months vs. 3.3 months; HR, 0.21; P = .02).

“You don't see this anywhere,” he said. “There's no drug in the world that could produce such response in patients who had already failed” bevacizumab.

The investigators also analyzed a surgery-naive group. “You know these are going to be poor responders, almost identical to [those with] bevacizumab failure,” Dr. Ram commented.

In this group of 38 patients, an intent-to-treat analysis showed that overall survival was 9.8 months with NovoTTF vs. 5.5 months with chemotherapy.

Patients also reported significantly better quality of life with NovoTTF than with chemotherapy. On the Quality of Life Symptom Scale, NovoTTF patients scored −34 and −35 on constipation and diarrhea, compared with scores of +77 and +50 for the chemotherapy group. Nausea and vomiting scores were 15 for the NovoTTF group and 61 for the chemotherapy group, and pain scores were −1 for the NovoTTF group and +63 for the chemotherapy group.

A quality of life analysis using the EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 instrument showed scores of 14 vs. −7 in favor of NovoTTF for cognitive functioning, and scores of 7 vs. 1 in favor of NovoTTF for emotional functioning.

“We do this to all our patients. We intoxicate them,” Dr. Ram said. “So even if NovoTTF did not extend survival, if it was equivalent to chemotherapy [for survival], it may still improve quality of life.”

Dr. Ram did not know the median length of time that the NovoTTF cohort wore the device, but an earlier phase II study followed some patients up to 59 months. He noted that “70% are still alive; that's unheard of.”

“There were concerns that patients might have more headaches or seizures, but there were none,” he added.

In the current study, the rate of adverse events related to the central nervous system was similar (66% for NovoTTF and 67% for chemotherapy). Seizures occurred in 15% of the NovoTTF group and 12% of the chemotherapy group, and headaches occurred in 18% and 13%, respectively.

“It's very interesting and exciting, even if we do not yet have enough definitive data,” commented Dr. Alba B. Brandes, moderator of the session and the chair of medical oncology at Azienda USL, a group of nine hospitals in and around Bologna, Italy.

The investigators have been criticized for repackaging their nonsignificant intent-to-treat results into per-protocol results that show significance, she said. “An intention-to-treat population and per-protocol population are two different things, and from a statistical point of view, it is sometimes difficult for the oncologic community to accept.” Despite those reservations, she said that the per-protocol observations should not be dismissed, because when they are analyzed in this way the results are highly significant.

Dr. Ram acknowledged that per-protocol analysis is unconventional, but “there is no precedent for this kind of therapy and I think we may need to redesign the way we assess results in the future. We cannot use the same guidelines and definitions we were traditionally using.”

Major Finding: 1-year overall survival in a subgroup of patients was significantly higher among those treated with NovoTTF-100A than it was in those who received chemotherapy (35.2% vs. 20.8%).

Data Source: Post hoc subgroup analysis of 237 patients with recurrent glioblastoma.

Disclosures: Dr. Zvi Ram disclosed that he is a consultant for NovoCure, which sponsored the trial and manufactures the device. Dr. Brandes said that she had no relevant financial disclosures.

MONTREAL – An investigational treatment for recurrent glioblastoma that delivers alternating electric fields through scalp electrodes has shown signs of improved survival in a post hoc analysis of results in particular subgroups of patients in a phase III trial.

Quality of life outcomes also favored patients who used the device, known as NovoTTF-100A, compared with those who received chemotherapy.

To date, reports about the device have elicited both antagonistic and enthusiastic reaction from oncologists, with “neither the enthusiasts nor the antagonists having significant basis for either kind of acute reaction,” Dr. Zvi Ram said in an interview after presenting the subgroup analyses at the meetingo “I think it is exciting that we're getting something completely new – a different, noninvasive modality with no side effects. I think we should be exhilarated.”

The device delivers low-amplitude “tumor treatment fields” of 100–300 kHz that have been shown in vitro to slow and reverse tumor cell proliferation by inhibiting mitosis, according to NovoCure Ltd., the manufacturer of the device and sponsor of the trial.

The portable device weighs about 6 pounds and connects to a battery pack. It is designed to be worn almost constantly, with a target of at least 20 hours of use each day.

In a phase III clinical trial presented earlier this year at the American Society of Clinical Oncology, an intent-to-treat analysis comparing NovoTTF vs. best-available chemotherapy found no statistical difference in 1-year overall survival (OS) among 237 recurrent glioblastoma patients randomized to either treatment.

However, a per-protocol analysis (which included only those patients who wore the device for at least 70% of the recommended time during the first month) showed a statistically significant benefit to NovoTTF in 1-year survival, compared with chemotherapy (29.5% vs. 19.1%, respectively; hazard ratio, 0.64; P = .01).

In the new post hoc analysis, a subgroup of 110 patients with a “good prognosis” (aged younger than 60 years, and with a Karnofsky performance status score greater than 80%) showed a “more robust” survival benefit than that seen in the overall intent-to-treat analysis, he said.

In this subgroup, patients treated with NovoTTF had a median survival of 9.2 months, vs. 6.6 months in those treated with chemotherapy (P less than .01). However, in the overall intent-to-treat group, median survival was 6.6 months and 6.0 months, respectively, he explained. Moreover, the 1-year OS in this subgroup was significantly higher in the NovoTTF group than in the chemotherapy group (35.2% vs. 20.8%, respectively; P less than .01), whereas the difference was nonsignificant in the larger analysis (23.6% vs. 20.7%).

Another subgroup analysis looked at patients who had previously failed treatment with bevacizumab (about 20% of the entire cohort). Both an intent-to-treat analysis and a per-protocol analysis showed significant OS advantages to NovoTTF, said Dr. Ram, chair of neurosurgery at Tel Aviv (Israel) Medical Center.

The median OS in 44 patients in the intent-to-treat group was 4 months with NovoTTF vs. 3.1 months with chemotherapy (HR, 0.43; P less than .02). NovoTTF also gave a significantly better median OS among 29 patients in the per-protocol analysis for this subgroup (6.3 months vs. 3.3 months; HR, 0.21; P = .02).

“You don't see this anywhere,” he said. “There's no drug in the world that could produce such response in patients who had already failed” bevacizumab.

The investigators also analyzed a surgery-naive group. “You know these are going to be poor responders, almost identical to [those with] bevacizumab failure,” Dr. Ram commented.

In this group of 38 patients, an intent-to-treat analysis showed that overall survival was 9.8 months with NovoTTF vs. 5.5 months with chemotherapy.

Patients also reported significantly better quality of life with NovoTTF than with chemotherapy. On the Quality of Life Symptom Scale, NovoTTF patients scored −34 and −35 on constipation and diarrhea, compared with scores of +77 and +50 for the chemotherapy group. Nausea and vomiting scores were 15 for the NovoTTF group and 61 for the chemotherapy group, and pain scores were −1 for the NovoTTF group and +63 for the chemotherapy group.

A quality of life analysis using the EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 instrument showed scores of 14 vs. −7 in favor of NovoTTF for cognitive functioning, and scores of 7 vs. 1 in favor of NovoTTF for emotional functioning.

“We do this to all our patients. We intoxicate them,” Dr. Ram said. “So even if NovoTTF did not extend survival, if it was equivalent to chemotherapy [for survival], it may still improve quality of life.”

Dr. Ram did not know the median length of time that the NovoTTF cohort wore the device, but an earlier phase II study followed some patients up to 59 months. He noted that “70% are still alive; that's unheard of.”

“There were concerns that patients might have more headaches or seizures, but there were none,” he added.

In the current study, the rate of adverse events related to the central nervous system was similar (66% for NovoTTF and 67% for chemotherapy). Seizures occurred in 15% of the NovoTTF group and 12% of the chemotherapy group, and headaches occurred in 18% and 13%, respectively.

“It's very interesting and exciting, even if we do not yet have enough definitive data,” commented Dr. Alba B. Brandes, moderator of the session and the chair of medical oncology at Azienda USL, a group of nine hospitals in and around Bologna, Italy.

The investigators have been criticized for repackaging their nonsignificant intent-to-treat results into per-protocol results that show significance, she said. “An intention-to-treat population and per-protocol population are two different things, and from a statistical point of view, it is sometimes difficult for the oncologic community to accept.” Despite those reservations, she said that the per-protocol observations should not be dismissed, because when they are analyzed in this way the results are highly significant.

Dr. Ram acknowledged that per-protocol analysis is unconventional, but “there is no precedent for this kind of therapy and I think we may need to redesign the way we assess results in the future. We cannot use the same guidelines and definitions we were traditionally using.”

MONTREAL – Bevacizumab-containing regimens continued to show efficacy against glioblastoma in recent reports of phase II trial results, but the trials' designs have come under fire by some neuro-oncologists.

Investigators from Duke University, Durham, N.C., reported at the meeting that adding bevacizumab (Avastin) and irinotecan (Camptosar) to a standard temozolomide (Temodar)–based chemoradiation regimen for newly diagnosed glioblastoma increased progression-free and overall survival by about 6 months, compared with historical controls.

In a separate RTOG (Radiation Therapy Oncology Group) study, investigators defined efficacy as a progression-free survival rate of 35% at 6 months in patients with recurrent glioblastoma. Both regimens in the noncomparative trial – bevacizumab with dose-dense temozolomide and bevacizumab with irinotecan – cleared the mark at 40% and 39%, respectively. Median overall survival was longer with the temozolomide partnership (9.4 months vs. 7.7 months with irinotecan), but the difference was not significant.

In 2009, the Food and Drug Administration approved bevacizumab as a single agent for the second-line treatment of glioblastoma, based on objective response rates in two single-arm trials.

Newly Diagnosed in Duke Study

The Genentech-sponsored study from Duke began with 125 patients (mean age, 56 years; 59% male) with newly diagnosed grade IV malignant glioblastoma multiforme (GBM), reported Dr. Annick Desjardins of the university's brain tumor center. Most (70%) had Karnofsky performance scores greater than 90%.

Between 2 and 4 weeks after resection, patients started 6 weeks of radiotherapy and daily temozolomide at 75 mg/m

In the second phase of the trial, 113 patients went on to receive 6–12 more weeks of bevacizumab at the same dosage, combined with temozolomide at 200 mg/m

The first phase of treatment was associated with minimal toxicity, the investigators recently reported (Int. J. Radiat. Oncol. Biol. Phys. 2010 Oct 30 [doi: 10.1016/j.ijrobp.2010.08.058]). Grade 4 thrombocytopenia occurred in 2.4%, neutropenia in 0.8%, central nervous system hemorrhage in 0.8%, and deep vein thrombosis and pulmonary embolism in 1.6%, said Dr. Desjardins.

Five patients did not complete the first phase (one patient with grade 2 CNS hemorrhage, two with pulmonary emboli, one with grade 4 pancytopenia, and one with wound dehiscence). Seven other patients did not go on to the second phase (three with tumor progression, two withdrawing because of fatigue, and one each with a bowel perforation and a rectal abscess). Patients in the second phase have been followed for a median of 28 months, said Dr. Desjardins.

A final analysis for the original cohort of 125 shows that median progression-free survival reached 14.2 months and median overall survival was 21.3 months. This compares with medians of 6.9 months and 15.9 months, respectively, that had been reported in the literature, she said.

Additionally, progression-free survival rates were 88% at 6 months, 64% at 1 year, and 16% at 2 years in the Duke cohort; overall survival rates were 94%, 82%, and 44%, respectively.

For all 125 patients enrolled, the overall serious toxicities included 1 CNS hemorrhage, 9 VTEs, 2 wound dehiscences, 1 bowel perforation, 17 grade 4 hematologic toxicities, 1 secondary malignancy, and 2 cases of pneumocystis pneumonia. There were four toxicity-related deaths.

RTOG Trial in Recurrent GBM

The noncomparative RTOG study enrolled patients with recurrent glioblastoma who had failed previous chemoradiation with temozolomide. In all, 57 patients were assigned to bevacizumab 10 mg/kg IV plus irinotecan 200 mg/kg every 2 weeks, and 58 were assigned to the same bevacizumab dose plus dose-dense temozolomide 75–100 mg/m

The two arms had different end points: safety with temozolomide and efficacy in the irinotecan arm, noted the presenter, Dr. Mark Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Hematologic toxicities were seen more in the temozolomide arm, whereas gastrointestinal toxicities predominated in the irinotecan arm, said Dr. Gilbert. One case of gastrointestinal perforation resulted in death.

“The primary objectives were met,” he reported. “We found that administering bevacizumab regimens in a cooperative group setting was feasible. We had acceptable toxicity with the combination of bevacizumab and dose-dense temozolomide, and it supported our use of this type of regimen in the up-front setting. And, in fact, the efficacy of both arms reached our target.”

Trials' Protocols Criticized

Both study designs were challenged at the meeting.

Session moderator Dr. Martin van den Bent contended that exposing all patients to the bevacizumab/irinotecan regimen in the Duke study – rather than randomizing patients to one agent or the other – makes it impossible to know which drug is preferable.

“It's flatly outrageous. It should not have been done,” Dr. van den Bent elaborated in an interview after the session. “What I find very disturbing is they did a very big study of 120 patients … but by doing it in an uncontrolled fashion, they ended up with an impossible interpretation of whether the irinotecan added to the bevacizumab made any difference.”

Dr. van den Bent, professor of neuro-oncology at the cancer center of Erasmus University in Rotterdam, the Netherlands, charged that Duke has a history of doing uncontrolled trials, but he also criticized the field's eagerness to embrace bevacizumab based on such trials.

“The use of bevacizumab at present is based on uncontrolled studies; it's been FDA approved on a scientifically not valid end point,” said Dr. van den Bent, a past chair of the EORTC (European Organisation for Research and Treatment of Cancer) Brain Tumor Group.

Study design also triggered a complaint with the RTOG trial. Dr. Gilbert cautioned that randomization was not consistent because of safety concerns with the temozolomide regimen. Until these were resolved, the initial 90 patients were randomized 2:1 favoring irinotecan. Consequently, the final 30 temozolomide patients were assigned to that arm without randomization.

For these reasons, “we cannot on the basis of this study tell which of the two treatments” is better, “or in fact whether a combination of chemotherapy with bevacizumab is better than bevacizumab alone,” he said, stressing that the study was not powered for comparison.

A member of the audience asked whether this wasn't “kind of a charade,” since comparisons were being made anyway.

“It's not a charade,” Dr. Gilbert replied, reiterating that the investigators had two separate goals: safety with temozolomide and efficacy with irinotecan. “It is what it is,” he said. “We certainly weren't going to power it, because we weren't interested particularly in the question of which was the better regimen.”

Genentech sponsored the study from Duke University. Dr. Desjardins reported no conflicts of interest. Dr. Gilbert disclosed research support from Merck and Genentech, and honoraria/advisory board participation with Merck and Genentech. Dr. van den Bent said he is a consultant for eight companies, including F. Hoffmann-La Roche, parent company of Genentech.

MONTREAL – Bevacizumab-containing regimens continued to show efficacy against glioblastoma in recent reports of phase II trial results, but the trials' designs have come under fire by some neuro-oncologists.

Investigators from Duke University, Durham, N.C., reported at the meeting that adding bevacizumab (Avastin) and irinotecan (Camptosar) to a standard temozolomide (Temodar)–based chemoradiation regimen for newly diagnosed glioblastoma increased progression-free and overall survival by about 6 months, compared with historical controls.

In a separate RTOG (Radiation Therapy Oncology Group) study, investigators defined efficacy as a progression-free survival rate of 35% at 6 months in patients with recurrent glioblastoma. Both regimens in the noncomparative trial – bevacizumab with dose-dense temozolomide and bevacizumab with irinotecan – cleared the mark at 40% and 39%, respectively. Median overall survival was longer with the temozolomide partnership (9.4 months vs. 7.7 months with irinotecan), but the difference was not significant.

In 2009, the Food and Drug Administration approved bevacizumab as a single agent for the second-line treatment of glioblastoma, based on objective response rates in two single-arm trials.

Newly Diagnosed in Duke Study

The Genentech-sponsored study from Duke began with 125 patients (mean age, 56 years; 59% male) with newly diagnosed grade IV malignant glioblastoma multiforme (GBM), reported Dr. Annick Desjardins of the university's brain tumor center. Most (70%) had Karnofsky performance scores greater than 90%.

Between 2 and 4 weeks after resection, patients started 6 weeks of radiotherapy and daily temozolomide at 75 mg/m

In the second phase of the trial, 113 patients went on to receive 6–12 more weeks of bevacizumab at the same dosage, combined with temozolomide at 200 mg/m

The first phase of treatment was associated with minimal toxicity, the investigators recently reported (Int. J. Radiat. Oncol. Biol. Phys. 2010 Oct 30 [doi: 10.1016/j.ijrobp.2010.08.058]). Grade 4 thrombocytopenia occurred in 2.4%, neutropenia in 0.8%, central nervous system hemorrhage in 0.8%, and deep vein thrombosis and pulmonary embolism in 1.6%, said Dr. Desjardins.

Five patients did not complete the first phase (one patient with grade 2 CNS hemorrhage, two with pulmonary emboli, one with grade 4 pancytopenia, and one with wound dehiscence). Seven other patients did not go on to the second phase (three with tumor progression, two withdrawing because of fatigue, and one each with a bowel perforation and a rectal abscess). Patients in the second phase have been followed for a median of 28 months, said Dr. Desjardins.

A final analysis for the original cohort of 125 shows that median progression-free survival reached 14.2 months and median overall survival was 21.3 months. This compares with medians of 6.9 months and 15.9 months, respectively, that had been reported in the literature, she said.

Additionally, progression-free survival rates were 88% at 6 months, 64% at 1 year, and 16% at 2 years in the Duke cohort; overall survival rates were 94%, 82%, and 44%, respectively.

For all 125 patients enrolled, the overall serious toxicities included 1 CNS hemorrhage, 9 VTEs, 2 wound dehiscences, 1 bowel perforation, 17 grade 4 hematologic toxicities, 1 secondary malignancy, and 2 cases of pneumocystis pneumonia. There were four toxicity-related deaths.

RTOG Trial in Recurrent GBM

The noncomparative RTOG study enrolled patients with recurrent glioblastoma who had failed previous chemoradiation with temozolomide. In all, 57 patients were assigned to bevacizumab 10 mg/kg IV plus irinotecan 200 mg/kg every 2 weeks, and 58 were assigned to the same bevacizumab dose plus dose-dense temozolomide 75–100 mg/m

The two arms had different end points: safety with temozolomide and efficacy in the irinotecan arm, noted the presenter, Dr. Mark Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Hematologic toxicities were seen more in the temozolomide arm, whereas gastrointestinal toxicities predominated in the irinotecan arm, said Dr. Gilbert. One case of gastrointestinal perforation resulted in death.

“The primary objectives were met,” he reported. “We found that administering bevacizumab regimens in a cooperative group setting was feasible. We had acceptable toxicity with the combination of bevacizumab and dose-dense temozolomide, and it supported our use of this type of regimen in the up-front setting. And, in fact, the efficacy of both arms reached our target.”

Trials' Protocols Criticized

Both study designs were challenged at the meeting.

Session moderator Dr. Martin van den Bent contended that exposing all patients to the bevacizumab/irinotecan regimen in the Duke study – rather than randomizing patients to one agent or the other – makes it impossible to know which drug is preferable.

“It's flatly outrageous. It should not have been done,” Dr. van den Bent elaborated in an interview after the session. “What I find very disturbing is they did a very big study of 120 patients … but by doing it in an uncontrolled fashion, they ended up with an impossible interpretation of whether the irinotecan added to the bevacizumab made any difference.”

Dr. van den Bent, professor of neuro-oncology at the cancer center of Erasmus University in Rotterdam, the Netherlands, charged that Duke has a history of doing uncontrolled trials, but he also criticized the field's eagerness to embrace bevacizumab based on such trials.

“The use of bevacizumab at present is based on uncontrolled studies; it's been FDA approved on a scientifically not valid end point,” said Dr. van den Bent, a past chair of the EORTC (European Organisation for Research and Treatment of Cancer) Brain Tumor Group.

Study design also triggered a complaint with the RTOG trial. Dr. Gilbert cautioned that randomization was not consistent because of safety concerns with the temozolomide regimen. Until these were resolved, the initial 90 patients were randomized 2:1 favoring irinotecan. Consequently, the final 30 temozolomide patients were assigned to that arm without randomization.

For these reasons, “we cannot on the basis of this study tell which of the two treatments” is better, “or in fact whether a combination of chemotherapy with bevacizumab is better than bevacizumab alone,” he said, stressing that the study was not powered for comparison.

A member of the audience asked whether this wasn't “kind of a charade,” since comparisons were being made anyway.

“It's not a charade,” Dr. Gilbert replied, reiterating that the investigators had two separate goals: safety with temozolomide and efficacy with irinotecan. “It is what it is,” he said. “We certainly weren't going to power it, because we weren't interested particularly in the question of which was the better regimen.”

Genentech sponsored the study from Duke University. Dr. Desjardins reported no conflicts of interest. Dr. Gilbert disclosed research support from Merck and Genentech, and honoraria/advisory board participation with Merck and Genentech. Dr. van den Bent said he is a consultant for eight companies, including F. Hoffmann-La Roche, parent company of Genentech.

MONTREAL – Bevacizumab-containing regimens continued to show efficacy against glioblastoma in recent reports of phase II trial results, but the trials' designs have come under fire by some neuro-oncologists.

Investigators from Duke University, Durham, N.C., reported at the meeting that adding bevacizumab (Avastin) and irinotecan (Camptosar) to a standard temozolomide (Temodar)–based chemoradiation regimen for newly diagnosed glioblastoma increased progression-free and overall survival by about 6 months, compared with historical controls.

In a separate RTOG (Radiation Therapy Oncology Group) study, investigators defined efficacy as a progression-free survival rate of 35% at 6 months in patients with recurrent glioblastoma. Both regimens in the noncomparative trial – bevacizumab with dose-dense temozolomide and bevacizumab with irinotecan – cleared the mark at 40% and 39%, respectively. Median overall survival was longer with the temozolomide partnership (9.4 months vs. 7.7 months with irinotecan), but the difference was not significant.

In 2009, the Food and Drug Administration approved bevacizumab as a single agent for the second-line treatment of glioblastoma, based on objective response rates in two single-arm trials.

Newly Diagnosed in Duke Study

The Genentech-sponsored study from Duke began with 125 patients (mean age, 56 years; 59% male) with newly diagnosed grade IV malignant glioblastoma multiforme (GBM), reported Dr. Annick Desjardins of the university's brain tumor center. Most (70%) had Karnofsky performance scores greater than 90%.

Between 2 and 4 weeks after resection, patients started 6 weeks of radiotherapy and daily temozolomide at 75 mg/m

In the second phase of the trial, 113 patients went on to receive 6–12 more weeks of bevacizumab at the same dosage, combined with temozolomide at 200 mg/m

The first phase of treatment was associated with minimal toxicity, the investigators recently reported (Int. J. Radiat. Oncol. Biol. Phys. 2010 Oct 30 [doi: 10.1016/j.ijrobp.2010.08.058]). Grade 4 thrombocytopenia occurred in 2.4%, neutropenia in 0.8%, central nervous system hemorrhage in 0.8%, and deep vein thrombosis and pulmonary embolism in 1.6%, said Dr. Desjardins.

Five patients did not complete the first phase (one patient with grade 2 CNS hemorrhage, two with pulmonary emboli, one with grade 4 pancytopenia, and one with wound dehiscence). Seven other patients did not go on to the second phase (three with tumor progression, two withdrawing because of fatigue, and one each with a bowel perforation and a rectal abscess). Patients in the second phase have been followed for a median of 28 months, said Dr. Desjardins.

A final analysis for the original cohort of 125 shows that median progression-free survival reached 14.2 months and median overall survival was 21.3 months. This compares with medians of 6.9 months and 15.9 months, respectively, that had been reported in the literature, she said.

Additionally, progression-free survival rates were 88% at 6 months, 64% at 1 year, and 16% at 2 years in the Duke cohort; overall survival rates were 94%, 82%, and 44%, respectively.

For all 125 patients enrolled, the overall serious toxicities included 1 CNS hemorrhage, 9 VTEs, 2 wound dehiscences, 1 bowel perforation, 17 grade 4 hematologic toxicities, 1 secondary malignancy, and 2 cases of pneumocystis pneumonia. There were four toxicity-related deaths.

RTOG Trial in Recurrent GBM

The noncomparative RTOG study enrolled patients with recurrent glioblastoma who had failed previous chemoradiation with temozolomide. In all, 57 patients were assigned to bevacizumab 10 mg/kg IV plus irinotecan 200 mg/kg every 2 weeks, and 58 were assigned to the same bevacizumab dose plus dose-dense temozolomide 75–100 mg/m

The two arms had different end points: safety with temozolomide and efficacy in the irinotecan arm, noted the presenter, Dr. Mark Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Hematologic toxicities were seen more in the temozolomide arm, whereas gastrointestinal toxicities predominated in the irinotecan arm, said Dr. Gilbert. One case of gastrointestinal perforation resulted in death.

“The primary objectives were met,” he reported. “We found that administering bevacizumab regimens in a cooperative group setting was feasible. We had acceptable toxicity with the combination of bevacizumab and dose-dense temozolomide, and it supported our use of this type of regimen in the up-front setting. And, in fact, the efficacy of both arms reached our target.”

Trials' Protocols Criticized

Both study designs were challenged at the meeting.

Session moderator Dr. Martin van den Bent contended that exposing all patients to the bevacizumab/irinotecan regimen in the Duke study – rather than randomizing patients to one agent or the other – makes it impossible to know which drug is preferable.

“It's flatly outrageous. It should not have been done,” Dr. van den Bent elaborated in an interview after the session. “What I find very disturbing is they did a very big study of 120 patients … but by doing it in an uncontrolled fashion, they ended up with an impossible interpretation of whether the irinotecan added to the bevacizumab made any difference.”

Dr. van den Bent, professor of neuro-oncology at the cancer center of Erasmus University in Rotterdam, the Netherlands, charged that Duke has a history of doing uncontrolled trials, but he also criticized the field's eagerness to embrace bevacizumab based on such trials.

“The use of bevacizumab at present is based on uncontrolled studies; it's been FDA approved on a scientifically not valid end point,” said Dr. van den Bent, a past chair of the EORTC (European Organisation for Research and Treatment of Cancer) Brain Tumor Group.

Study design also triggered a complaint with the RTOG trial. Dr. Gilbert cautioned that randomization was not consistent because of safety concerns with the temozolomide regimen. Until these were resolved, the initial 90 patients were randomized 2:1 favoring irinotecan. Consequently, the final 30 temozolomide patients were assigned to that arm without randomization.

For these reasons, “we cannot on the basis of this study tell which of the two treatments” is better, “or in fact whether a combination of chemotherapy with bevacizumab is better than bevacizumab alone,” he said, stressing that the study was not powered for comparison.

A member of the audience asked whether this wasn't “kind of a charade,” since comparisons were being made anyway.

“It's not a charade,” Dr. Gilbert replied, reiterating that the investigators had two separate goals: safety with temozolomide and efficacy with irinotecan. “It is what it is,” he said. “We certainly weren't going to power it, because we weren't interested particularly in the question of which was the better regimen.”

Genentech sponsored the study from Duke University. Dr. Desjardins reported no conflicts of interest. Dr. Gilbert disclosed research support from Merck and Genentech, and honoraria/advisory board participation with Merck and Genentech. Dr. van den Bent said he is a consultant for eight companies, including F. Hoffmann-La Roche, parent company of Genentech.

Gamma-secretase inhibitors could play an important role in augmenting the effectiveness of temozolomide chemotherapy for glioblastoma multiforme if the results obtained in recent in vitro, ex vivo, and in vivo experiments are supported in future studies.

Although temozolomide (TMZ) has increased the 2-year survival rate of patients with glioblastoma multiforme (GBM) when it is used in combination with surgical resection and radiotherapy, some cells still escape treatment in most patients and contribute to local tumor recurrence. Gamma-secretase inhibitors (GSIs) are an attractive therapeutic option because they have been found in previous studies to stop both glioblastoma cell growth and the formation of glioblastoma neurospheres by blocking the Notch signaling pathway, which is commonly overexpressed in glioblastoma cells, wrote Candace A. Gilbert and her colleagues at the University of Massachusetts, Worcester (Cancer Res. 2010 Aug. 10 [doi:10.1158/0008-5472.CAN-10-1378]).

Before Ms. Gilbert and her associates tested the combination of TMZ and a GSI in vivo, they tested TMZ alone, a GSI alone, and both together on neurosphere cultures derived from patients' GBMs. Although GSI treatment alone decreased Notch pathway signaling and reduced neurosphere formation, it could not stop the proliferation of GBM cells and the formation of secondary neurospheres. And although treatment with TMZ alone and combined treatment with TMZ and a GSI yielded similar decreases in initial neurosphere formation, cultures treated with the combination recovered to a smaller size, and there were fewer of them than was the case for those treated with TMZ alone. When these neurosphere cultures were dissociated to single cells and replated, the cells that underwent combination treatment formed far fewer secondary neurospheres than did those treated with only TMZ. Treatment with both drugs also led to significantly fewer cells in each neurosphere that were capable of self-renewal.

Further in vitro experiments of the combination of drugs showed that a single dose of a GSI could reduce neurosphere recovery and the formation of secondary neurospheres only when the GSI was administered 24 hours after TMZ, in comparison with TMZ alone.

When the tumor cells were treated and then injected subcutaneously into immunocompromised mice, the researchers observed palpable tumor growth in very few mice that received cells treated with TMZ and a GSI (tumor latencies, 43-96 days), compared with tumor growth in all mice that received cells treated with a GSI alone (latencies, 3-16 days) and growth in nearly all mice that received cells treated with TMZ alone (latencies, 25-43 days).

In another group of immunocompromised mice, tumor cells that were injected subcutaneously were allowed to grow to 150 mm

All tumor masses progressed (doubled in size) in mice that received only TMZ.

“Because Notch activity is associated with GBM stem cell function and survival, and the cells that survive TMZ-only treatment are capable of self-renewal and tumor initiation, it is probable that the cells targeted by TMZ plus GSI treatment possess a cancer stem cell phenotype,” the researchers wrote.

They suggested that the variability of response to combined treatment in the in vivo studies could have been due to a TMZ concentration that was not “high enough to induce a cell cycle arrest in all the cells capable of recovery, which could hinder GSI enhancement,” or a “slight variability” in food consumption.

The need for only a single dose of a GSI to enhance TMZ therapy is beneficial, the researchers noted, because GSIs can cause cytotoxicity in the gastrointestinal tract. They found no change in the weight of the mice during combined treatment.

“These studies suggest a role for TMZ plus GSI therapy to reduce recurrences in patients with low tumor burden after surgical resection of the bulk tumor,” wrote the investigators, who acknowledged that they ultimately need to include radiation in their treatment schedule to see how it contributes to combination therapy with TMZ and GSIs.

The National Institutes of Health and the CVIP Technology Development Fund funded the research. The investigators had no conflicts of interest to disclose.

Research report by Managing Editor, Jeff Evans.

Adviser's Viewpoint

A Springboard to Future Treatments

Since 2005, the treatment standard for GBM has been concomitant TMZ with radiotherapy followed by adjuvant TMZ. This treatment showed slightly increased overall survival, compared with radiotherapy alone. However, the most striking finding in support of this treatment was the 2-year survival rate of 26.5%, which was higher than any prior treatment regimen had shown. The time to progression on the aforementioned regimen is about 6 months, which points to the refractory and aggressive nature of this tumor. Despite the progress made with up-front therapy, researchers in the field continue to struggle with how to prevent tumor recurrence, and we remain limited in our treatment options for recurrent disease.

Thus far, bevacizumab has been the only agent approved by the Food and Drug Administration for use in the setting of recurrent GBM. Studies are currently underway to assess the up-front efficacy of using bevacizumab with radiotherapy and TMZ. Given the dismal prognosis for this patient population, novel agents are needed not only to augment up-front therapy to prevent recurrence but also to provide further treatment options in the recurrent setting.

Ms. Gilbert and colleagues conducted an eloquent study using a novel GSI to assess influence on neurosphere replication in the pre-, adjunct, and post-TMZ treatment periods. The remarkable in vitro and in vivo data suggest that GSI and TMZ act together to halt neurosphere replication, and that administering a GSI after TMZ may have the maximum impact in affecting neurosphere repopulation. These data suggest that GSIs may indeed have an impact on glioblastoma recurrence and time to progression.

As the authors point out, future studies to assess the total impact of the GSI in the GBM population will need to incorporate irradiation in addition to TMZ to reflect a more accurate sense of the full effect and toxicity of the GSI. Toxicity was measured in this study by rodent weight; according to the data provided, it seemed well tolerated with TMZ. The authors suggest that GSIs may also improve the impact of irradiation, which may further reduce treatment toxicity. This study certainly provides a springboard for considering future directions in the use of GSIs and may indeed provide further treatment options for this patient population, in whom options are greatly needed.

ALYX B. PORTER, M.D., is a neuro-oncologist at the Mayo Clinic in Arizona. She has no relevant disclosures.

Gamma-secretase inhibitors could play an important role in augmenting the effectiveness of temozolomide chemotherapy for glioblastoma multiforme if the results obtained in recent in vitro, ex vivo, and in vivo experiments are supported in future studies.

Although temozolomide (TMZ) has increased the 2-year survival rate of patients with glioblastoma multiforme (GBM) when it is used in combination with surgical resection and radiotherapy, some cells still escape treatment in most patients and contribute to local tumor recurrence. Gamma-secretase inhibitors (GSIs) are an attractive therapeutic option because they have been found in previous studies to stop both glioblastoma cell growth and the formation of glioblastoma neurospheres by blocking the Notch signaling pathway, which is commonly overexpressed in glioblastoma cells, wrote Candace A. Gilbert and her colleagues at the University of Massachusetts, Worcester (Cancer Res. 2010 Aug. 10 [doi:10.1158/0008-5472.CAN-10-1378]).

Before Ms. Gilbert and her associates tested the combination of TMZ and a GSI in vivo, they tested TMZ alone, a GSI alone, and both together on neurosphere cultures derived from patients' GBMs. Although GSI treatment alone decreased Notch pathway signaling and reduced neurosphere formation, it could not stop the proliferation of GBM cells and the formation of secondary neurospheres. And although treatment with TMZ alone and combined treatment with TMZ and a GSI yielded similar decreases in initial neurosphere formation, cultures treated with the combination recovered to a smaller size, and there were fewer of them than was the case for those treated with TMZ alone. When these neurosphere cultures were dissociated to single cells and replated, the cells that underwent combination treatment formed far fewer secondary neurospheres than did those treated with only TMZ. Treatment with both drugs also led to significantly fewer cells in each neurosphere that were capable of self-renewal.

Further in vitro experiments of the combination of drugs showed that a single dose of a GSI could reduce neurosphere recovery and the formation of secondary neurospheres only when the GSI was administered 24 hours after TMZ, in comparison with TMZ alone.

When the tumor cells were treated and then injected subcutaneously into immunocompromised mice, the researchers observed palpable tumor growth in very few mice that received cells treated with TMZ and a GSI (tumor latencies, 43-96 days), compared with tumor growth in all mice that received cells treated with a GSI alone (latencies, 3-16 days) and growth in nearly all mice that received cells treated with TMZ alone (latencies, 25-43 days).

In another group of immunocompromised mice, tumor cells that were injected subcutaneously were allowed to grow to 150 mm

All tumor masses progressed (doubled in size) in mice that received only TMZ.

“Because Notch activity is associated with GBM stem cell function and survival, and the cells that survive TMZ-only treatment are capable of self-renewal and tumor initiation, it is probable that the cells targeted by TMZ plus GSI treatment possess a cancer stem cell phenotype,” the researchers wrote.

They suggested that the variability of response to combined treatment in the in vivo studies could have been due to a TMZ concentration that was not “high enough to induce a cell cycle arrest in all the cells capable of recovery, which could hinder GSI enhancement,” or a “slight variability” in food consumption.

The need for only a single dose of a GSI to enhance TMZ therapy is beneficial, the researchers noted, because GSIs can cause cytotoxicity in the gastrointestinal tract. They found no change in the weight of the mice during combined treatment.

“These studies suggest a role for TMZ plus GSI therapy to reduce recurrences in patients with low tumor burden after surgical resection of the bulk tumor,” wrote the investigators, who acknowledged that they ultimately need to include radiation in their treatment schedule to see how it contributes to combination therapy with TMZ and GSIs.

The National Institutes of Health and the CVIP Technology Development Fund funded the research. The investigators had no conflicts of interest to disclose.

Research report by Managing Editor, Jeff Evans.

Adviser's Viewpoint

A Springboard to Future Treatments

Since 2005, the treatment standard for GBM has been concomitant TMZ with radiotherapy followed by adjuvant TMZ. This treatment showed slightly increased overall survival, compared with radiotherapy alone. However, the most striking finding in support of this treatment was the 2-year survival rate of 26.5%, which was higher than any prior treatment regimen had shown. The time to progression on the aforementioned regimen is about 6 months, which points to the refractory and aggressive nature of this tumor. Despite the progress made with up-front therapy, researchers in the field continue to struggle with how to prevent tumor recurrence, and we remain limited in our treatment options for recurrent disease.

Thus far, bevacizumab has been the only agent approved by the Food and Drug Administration for use in the setting of recurrent GBM. Studies are currently underway to assess the up-front efficacy of using bevacizumab with radiotherapy and TMZ. Given the dismal prognosis for this patient population, novel agents are needed not only to augment up-front therapy to prevent recurrence but also to provide further treatment options in the recurrent setting.

Ms. Gilbert and colleagues conducted an eloquent study using a novel GSI to assess influence on neurosphere replication in the pre-, adjunct, and post-TMZ treatment periods. The remarkable in vitro and in vivo data suggest that GSI and TMZ act together to halt neurosphere replication, and that administering a GSI after TMZ may have the maximum impact in affecting neurosphere repopulation. These data suggest that GSIs may indeed have an impact on glioblastoma recurrence and time to progression.

As the authors point out, future studies to assess the total impact of the GSI in the GBM population will need to incorporate irradiation in addition to TMZ to reflect a more accurate sense of the full effect and toxicity of the GSI. Toxicity was measured in this study by rodent weight; according to the data provided, it seemed well tolerated with TMZ. The authors suggest that GSIs may also improve the impact of irradiation, which may further reduce treatment toxicity. This study certainly provides a springboard for considering future directions in the use of GSIs and may indeed provide further treatment options for this patient population, in whom options are greatly needed.

ALYX B. PORTER, M.D., is a neuro-oncologist at the Mayo Clinic in Arizona. She has no relevant disclosures.

Gamma-secretase inhibitors could play an important role in augmenting the effectiveness of temozolomide chemotherapy for glioblastoma multiforme if the results obtained in recent in vitro, ex vivo, and in vivo experiments are supported in future studies.

Although temozolomide (TMZ) has increased the 2-year survival rate of patients with glioblastoma multiforme (GBM) when it is used in combination with surgical resection and radiotherapy, some cells still escape treatment in most patients and contribute to local tumor recurrence. Gamma-secretase inhibitors (GSIs) are an attractive therapeutic option because they have been found in previous studies to stop both glioblastoma cell growth and the formation of glioblastoma neurospheres by blocking the Notch signaling pathway, which is commonly overexpressed in glioblastoma cells, wrote Candace A. Gilbert and her colleagues at the University of Massachusetts, Worcester (Cancer Res. 2010 Aug. 10 [doi:10.1158/0008-5472.CAN-10-1378]).

Before Ms. Gilbert and her associates tested the combination of TMZ and a GSI in vivo, they tested TMZ alone, a GSI alone, and both together on neurosphere cultures derived from patients' GBMs. Although GSI treatment alone decreased Notch pathway signaling and reduced neurosphere formation, it could not stop the proliferation of GBM cells and the formation of secondary neurospheres. And although treatment with TMZ alone and combined treatment with TMZ and a GSI yielded similar decreases in initial neurosphere formation, cultures treated with the combination recovered to a smaller size, and there were fewer of them than was the case for those treated with TMZ alone. When these neurosphere cultures were dissociated to single cells and replated, the cells that underwent combination treatment formed far fewer secondary neurospheres than did those treated with only TMZ. Treatment with both drugs also led to significantly fewer cells in each neurosphere that were capable of self-renewal.

Further in vitro experiments of the combination of drugs showed that a single dose of a GSI could reduce neurosphere recovery and the formation of secondary neurospheres only when the GSI was administered 24 hours after TMZ, in comparison with TMZ alone.

When the tumor cells were treated and then injected subcutaneously into immunocompromised mice, the researchers observed palpable tumor growth in very few mice that received cells treated with TMZ and a GSI (tumor latencies, 43-96 days), compared with tumor growth in all mice that received cells treated with a GSI alone (latencies, 3-16 days) and growth in nearly all mice that received cells treated with TMZ alone (latencies, 25-43 days).

In another group of immunocompromised mice, tumor cells that were injected subcutaneously were allowed to grow to 150 mm

All tumor masses progressed (doubled in size) in mice that received only TMZ.

“Because Notch activity is associated with GBM stem cell function and survival, and the cells that survive TMZ-only treatment are capable of self-renewal and tumor initiation, it is probable that the cells targeted by TMZ plus GSI treatment possess a cancer stem cell phenotype,” the researchers wrote.

They suggested that the variability of response to combined treatment in the in vivo studies could have been due to a TMZ concentration that was not “high enough to induce a cell cycle arrest in all the cells capable of recovery, which could hinder GSI enhancement,” or a “slight variability” in food consumption.

The need for only a single dose of a GSI to enhance TMZ therapy is beneficial, the researchers noted, because GSIs can cause cytotoxicity in the gastrointestinal tract. They found no change in the weight of the mice during combined treatment.

“These studies suggest a role for TMZ plus GSI therapy to reduce recurrences in patients with low tumor burden after surgical resection of the bulk tumor,” wrote the investigators, who acknowledged that they ultimately need to include radiation in their treatment schedule to see how it contributes to combination therapy with TMZ and GSIs.

The National Institutes of Health and the CVIP Technology Development Fund funded the research. The investigators had no conflicts of interest to disclose.

Research report by Managing Editor, Jeff Evans.

Adviser's Viewpoint

A Springboard to Future Treatments

Since 2005, the treatment standard for GBM has been concomitant TMZ with radiotherapy followed by adjuvant TMZ. This treatment showed slightly increased overall survival, compared with radiotherapy alone. However, the most striking finding in support of this treatment was the 2-year survival rate of 26.5%, which was higher than any prior treatment regimen had shown. The time to progression on the aforementioned regimen is about 6 months, which points to the refractory and aggressive nature of this tumor. Despite the progress made with up-front therapy, researchers in the field continue to struggle with how to prevent tumor recurrence, and we remain limited in our treatment options for recurrent disease.

Thus far, bevacizumab has been the only agent approved by the Food and Drug Administration for use in the setting of recurrent GBM. Studies are currently underway to assess the up-front efficacy of using bevacizumab with radiotherapy and TMZ. Given the dismal prognosis for this patient population, novel agents are needed not only to augment up-front therapy to prevent recurrence but also to provide further treatment options in the recurrent setting.

Ms. Gilbert and colleagues conducted an eloquent study using a novel GSI to assess influence on neurosphere replication in the pre-, adjunct, and post-TMZ treatment periods. The remarkable in vitro and in vivo data suggest that GSI and TMZ act together to halt neurosphere replication, and that administering a GSI after TMZ may have the maximum impact in affecting neurosphere repopulation. These data suggest that GSIs may indeed have an impact on glioblastoma recurrence and time to progression.

As the authors point out, future studies to assess the total impact of the GSI in the GBM population will need to incorporate irradiation in addition to TMZ to reflect a more accurate sense of the full effect and toxicity of the GSI. Toxicity was measured in this study by rodent weight; according to the data provided, it seemed well tolerated with TMZ. The authors suggest that GSIs may also improve the impact of irradiation, which may further reduce treatment toxicity. This study certainly provides a springboard for considering future directions in the use of GSIs and may indeed provide further treatment options for this patient population, in whom options are greatly needed.

ALYX B. PORTER, M.D., is a neuro-oncologist at the Mayo Clinic in Arizona. She has no relevant disclosures.

Major Finding: INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

Data Source: A retrospective analysis of children in the International Neuroblastoma Risk Group database.

Disclosures: The study was supported by the Little Heroes Pediatric Cancer Research Foundation, the Forbeck Foundation, and a grant from the National Institutes of Health. Dr. London and her associates reported no conflicts of interest.

CHICAGO — Time to relapse is highly predictive of overall survival post relapse in children with neuroblastoma, according to an analysis of 2,266 children in the International Neuroblastoma Risk Group database.

The analysis identified other factors prognostic of overall survival post relapse as well as a small proportion of relapsed patients who are salvageable, Wendy B. London, Ph.D., reported at the meeting.

Currently, clinicians do not know how to identify which patients are more likely to respond to postrelapse therapy and have difficulty in interpreting time to relapse because neuroblastoma is a heterogeneous disease, she said.

The median time to relapse among the 2,266 children was 13.2 months, with a wide range from 1 day to 11.4 years.

All told, 73% of children who relapsed were aged 18 months or older, 72% were International Neuroblastoma Staging System (INSS) stage 4, and 33% had amplified MYCN oncogene expression.

Overall survival at 5 years was 20%.

It was not possible to categorize time to relapse using a simple 1-year cutoff, said Dr. London, director of biostatistics at Children's Hospital Boston.

The risk of death was about the same for children who relapsed within the first 6 months as it was for those who relapsed at 18-24 months. The risk of death was highest in those who relapsed between 6 and 18 months.

All three groups had a significantly higher risk of death, compared with patients who relapsed after 36 months (P less than .001).

The association between time to relapse and overall survival appears to be driven by stage 3, 4, and MYCN-amplified patients, Dr. London said.

In a survival tree regression analysis that adjusted for time to relapse, disease stage was identified as the most highly significant variable for survival post relapse. INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

“Aggressive disease that advances unhindered by treatment has a highly predictable time course and ultimate death; we already knew this, but now we're able to describe it quantitatively,” she said.

Upon further analysis, three cohorts emerged as salvageable after relapse:

▸ Patients who are stage 4, with nonamplified MYCN, and less than 18 months of age.

▸ Patients who are stage 1, 2, 3, or 4S with MYCN amplification.

▸ Patients who are stage 1, 2, 3, or 4S with nonamplified MYCN and undifferentiated grade histology.

Patients who had stage 4 disease and MYCN amplification had a 5-year survival of 4%, compared with 12% for stage 4 patients with nonamplified MYCN.

Time to first relapse as a predictor of survival is important for two reasons, said Dr. Andrew Pearson, chair of pediatric oncology at the Institute of Cancer Research and the Royal Marsden Hospital in London, who was invited to discuss the findings. It can be used to stratify and/or describe patients in early clinical trials and to identify a salvageable population post relapse.

“In the past, I'm sure that some agents have had a negative response in early clinical studies because a group of very poor prognosis patients were included,” he said.

The study findings will also be utilized by the International Neuroblastoma Risk Group, which is nearing completion of standardized international criteria for eligibility and response for phase II studies in neuroblastoma, he said.

In multivariable analysis, factors at diagnosis that were independently predictive of overall survival post relapse were stage 4 (hazard ratio, 6.9); stage 3 (HR, 4.3); stage 4S (HR, 3.5); MYCN amplification (HR, 2.4); age less than 18 months (HR, 1.6); and time to relapse less than 12 months (HR, 2.0) – all with a P value less than 0.0001, Dr. London said.

Time to relapse was predictive of survival post relapse in patients with stage 1, stage 2, or no MYCN amplification, but it was not independently predictive, she said.

My Take

Time to Relapse Useful for Determining Trial Eligibility

The observation that time to relapse predicts survival in neuroblastoma is made possible by the analysis of a large international collaborative database. Given the unique biology of neuroblastoma and the extreme clinical heterogeneity that impacts its natural history despite therapy and initial response to therapy, this finding will be important as new agents become available for investigation in this disease and especially when nontraditional end points such as time to progression and progression-free survival are considered.

In addition, refining and enriching patient populations for some degree of biological homogeneity is important, not only for the purpose of accurately defining activity of a specific investigational agent in this specific disease, but also for potentially identifying a group of patients with relapsed disease who may be candidates for more conventional or standard salvage therapy approaches. This will also aid in defining eligibility criteria and estimating accrual requirements for investigational approaches.

Vitals

GREGORY H. REAMAN, M.D., is chair of the United States–based Children's Oncology Group. He is also a professor of pediatrics at George Washington University School of Medicine and Health and member of the Division of Hematology-Oncology at the Children's National Medical Center, both in Washington.

Major Finding: INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

Data Source: A retrospective analysis of children in the International Neuroblastoma Risk Group database.

Disclosures: The study was supported by the Little Heroes Pediatric Cancer Research Foundation, the Forbeck Foundation, and a grant from the National Institutes of Health. Dr. London and her associates reported no conflicts of interest.

CHICAGO — Time to relapse is highly predictive of overall survival post relapse in children with neuroblastoma, according to an analysis of 2,266 children in the International Neuroblastoma Risk Group database.

The analysis identified other factors prognostic of overall survival post relapse as well as a small proportion of relapsed patients who are salvageable, Wendy B. London, Ph.D., reported at the meeting.

Currently, clinicians do not know how to identify which patients are more likely to respond to postrelapse therapy and have difficulty in interpreting time to relapse because neuroblastoma is a heterogeneous disease, she said.

The median time to relapse among the 2,266 children was 13.2 months, with a wide range from 1 day to 11.4 years.

All told, 73% of children who relapsed were aged 18 months or older, 72% were International Neuroblastoma Staging System (INSS) stage 4, and 33% had amplified MYCN oncogene expression.

Overall survival at 5 years was 20%.

It was not possible to categorize time to relapse using a simple 1-year cutoff, said Dr. London, director of biostatistics at Children's Hospital Boston.

The risk of death was about the same for children who relapsed within the first 6 months as it was for those who relapsed at 18-24 months. The risk of death was highest in those who relapsed between 6 and 18 months.

All three groups had a significantly higher risk of death, compared with patients who relapsed after 36 months (P less than .001).

The association between time to relapse and overall survival appears to be driven by stage 3, 4, and MYCN-amplified patients, Dr. London said.

In a survival tree regression analysis that adjusted for time to relapse, disease stage was identified as the most highly significant variable for survival post relapse. INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

“Aggressive disease that advances unhindered by treatment has a highly predictable time course and ultimate death; we already knew this, but now we're able to describe it quantitatively,” she said.

Upon further analysis, three cohorts emerged as salvageable after relapse:

▸ Patients who are stage 4, with nonamplified MYCN, and less than 18 months of age.

▸ Patients who are stage 1, 2, 3, or 4S with MYCN amplification.

▸ Patients who are stage 1, 2, 3, or 4S with nonamplified MYCN and undifferentiated grade histology.

Patients who had stage 4 disease and MYCN amplification had a 5-year survival of 4%, compared with 12% for stage 4 patients with nonamplified MYCN.

Time to first relapse as a predictor of survival is important for two reasons, said Dr. Andrew Pearson, chair of pediatric oncology at the Institute of Cancer Research and the Royal Marsden Hospital in London, who was invited to discuss the findings. It can be used to stratify and/or describe patients in early clinical trials and to identify a salvageable population post relapse.

“In the past, I'm sure that some agents have had a negative response in early clinical studies because a group of very poor prognosis patients were included,” he said.

The study findings will also be utilized by the International Neuroblastoma Risk Group, which is nearing completion of standardized international criteria for eligibility and response for phase II studies in neuroblastoma, he said.

In multivariable analysis, factors at diagnosis that were independently predictive of overall survival post relapse were stage 4 (hazard ratio, 6.9); stage 3 (HR, 4.3); stage 4S (HR, 3.5); MYCN amplification (HR, 2.4); age less than 18 months (HR, 1.6); and time to relapse less than 12 months (HR, 2.0) – all with a P value less than 0.0001, Dr. London said.

Time to relapse was predictive of survival post relapse in patients with stage 1, stage 2, or no MYCN amplification, but it was not independently predictive, she said.

My Take

Time to Relapse Useful for Determining Trial Eligibility

The observation that time to relapse predicts survival in neuroblastoma is made possible by the analysis of a large international collaborative database. Given the unique biology of neuroblastoma and the extreme clinical heterogeneity that impacts its natural history despite therapy and initial response to therapy, this finding will be important as new agents become available for investigation in this disease and especially when nontraditional end points such as time to progression and progression-free survival are considered.

In addition, refining and enriching patient populations for some degree of biological homogeneity is important, not only for the purpose of accurately defining activity of a specific investigational agent in this specific disease, but also for potentially identifying a group of patients with relapsed disease who may be candidates for more conventional or standard salvage therapy approaches. This will also aid in defining eligibility criteria and estimating accrual requirements for investigational approaches.

Vitals

GREGORY H. REAMAN, M.D., is chair of the United States–based Children's Oncology Group. He is also a professor of pediatrics at George Washington University School of Medicine and Health and member of the Division of Hematology-Oncology at the Children's National Medical Center, both in Washington.

Major Finding: INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

Data Source: A retrospective analysis of children in the International Neuroblastoma Risk Group database.

Disclosures: The study was supported by the Little Heroes Pediatric Cancer Research Foundation, the Forbeck Foundation, and a grant from the National Institutes of Health. Dr. London and her associates reported no conflicts of interest.

CHICAGO — Time to relapse is highly predictive of overall survival post relapse in children with neuroblastoma, according to an analysis of 2,266 children in the International Neuroblastoma Risk Group database.

The analysis identified other factors prognostic of overall survival post relapse as well as a small proportion of relapsed patients who are salvageable, Wendy B. London, Ph.D., reported at the meeting.

Currently, clinicians do not know how to identify which patients are more likely to respond to postrelapse therapy and have difficulty in interpreting time to relapse because neuroblastoma is a heterogeneous disease, she said.

The median time to relapse among the 2,266 children was 13.2 months, with a wide range from 1 day to 11.4 years.

All told, 73% of children who relapsed were aged 18 months or older, 72% were International Neuroblastoma Staging System (INSS) stage 4, and 33% had amplified MYCN oncogene expression.

Overall survival at 5 years was 20%.

It was not possible to categorize time to relapse using a simple 1-year cutoff, said Dr. London, director of biostatistics at Children's Hospital Boston.

The risk of death was about the same for children who relapsed within the first 6 months as it was for those who relapsed at 18-24 months. The risk of death was highest in those who relapsed between 6 and 18 months.

All three groups had a significantly higher risk of death, compared with patients who relapsed after 36 months (P less than .001).

The association between time to relapse and overall survival appears to be driven by stage 3, 4, and MYCN-amplified patients, Dr. London said.

In a survival tree regression analysis that adjusted for time to relapse, disease stage was identified as the most highly significant variable for survival post relapse. INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

“Aggressive disease that advances unhindered by treatment has a highly predictable time course and ultimate death; we already knew this, but now we're able to describe it quantitatively,” she said.

Upon further analysis, three cohorts emerged as salvageable after relapse:

▸ Patients who are stage 4, with nonamplified MYCN, and less than 18 months of age.

▸ Patients who are stage 1, 2, 3, or 4S with MYCN amplification.

▸ Patients who are stage 1, 2, 3, or 4S with nonamplified MYCN and undifferentiated grade histology.

Patients who had stage 4 disease and MYCN amplification had a 5-year survival of 4%, compared with 12% for stage 4 patients with nonamplified MYCN.

Time to first relapse as a predictor of survival is important for two reasons, said Dr. Andrew Pearson, chair of pediatric oncology at the Institute of Cancer Research and the Royal Marsden Hospital in London, who was invited to discuss the findings. It can be used to stratify and/or describe patients in early clinical trials and to identify a salvageable population post relapse.

“In the past, I'm sure that some agents have had a negative response in early clinical studies because a group of very poor prognosis patients were included,” he said.

The study findings will also be utilized by the International Neuroblastoma Risk Group, which is nearing completion of standardized international criteria for eligibility and response for phase II studies in neuroblastoma, he said.

In multivariable analysis, factors at diagnosis that were independently predictive of overall survival post relapse were stage 4 (hazard ratio, 6.9); stage 3 (HR, 4.3); stage 4S (HR, 3.5); MYCN amplification (HR, 2.4); age less than 18 months (HR, 1.6); and time to relapse less than 12 months (HR, 2.0) – all with a P value less than 0.0001, Dr. London said.

Time to relapse was predictive of survival post relapse in patients with stage 1, stage 2, or no MYCN amplification, but it was not independently predictive, she said.

My Take

Time to Relapse Useful for Determining Trial Eligibility

The observation that time to relapse predicts survival in neuroblastoma is made possible by the analysis of a large international collaborative database. Given the unique biology of neuroblastoma and the extreme clinical heterogeneity that impacts its natural history despite therapy and initial response to therapy, this finding will be important as new agents become available for investigation in this disease and especially when nontraditional end points such as time to progression and progression-free survival are considered.

In addition, refining and enriching patient populations for some degree of biological homogeneity is important, not only for the purpose of accurately defining activity of a specific investigational agent in this specific disease, but also for potentially identifying a group of patients with relapsed disease who may be candidates for more conventional or standard salvage therapy approaches. This will also aid in defining eligibility criteria and estimating accrual requirements for investigational approaches.

Vitals

GREGORY H. REAMAN, M.D., is chair of the United States–based Children's Oncology Group. He is also a professor of pediatrics at George Washington University School of Medicine and Health and member of the Division of Hematology-Oncology at the Children's National Medical Center, both in Washington.

Major Finding: The 12-month rate of survival was 38% with both bevacizumab alone and bevacizumab plus irinotecan in updated analyses, and no new adverse effects were noted.

Data Source: A randomized, noncomparative, open-label phase II trial among 167 patients with relapsed glioblastoma multiforme (the BRAIN trial).

Disclosures: Genentech sponsored the trial. Some of the investigators are employees of or consultants to Genentech, or have received honoraria or research funding from the company. Dr. Brandes disclosed having a consultant or advisory role with and receiving honoraria from Roche, which owns Genentech.

CHICAGO — Bevacizumab, alone or in combination with irinotecan, is generally safe and active in patients with relapsed glioblastoma, according to updated results of the phase II BRAIN trial.

“Up to 16% of patients who received bevacizumab-based therapy remained alive at 30 months,” lead investigator Dr. Timothy Cloughesy reported. “The incidence of selected [adverse events] in the updated safety data was consistent with what was previously reported—there were no new safety signals that were identified.”

The Study to Evaluate Bevacizumab Alone or in Combination With Irinotecan for Treatment of Glioblastoma Multiforme (BRAIN) trial's efficacy results compare favorably with those of similar trials testing other regimens, Dr. Cloughesy said: the 12-month survival rate was 38% whereas it has been 14%-27% with cytotoxic agents such as temozolomide (Temo-dar) or lomustine (CCNU).

Sorting out the specific contributions of bevacizumab (Avastin) and irinotecan (Camptosar) to the observed outcomes is difficult because of the trial's design, he said. However, “when we look at what is providing the majority of the effect that we are seeing, I think it is coming from bevacizumab.”

The multicenter trial, sponsored by Genentech (manufacturer of bevacizumab), opened in July 2006 to patients with glioblastoma in first or second relapse who had previously received radiation therapy and temozolomide.

They were randomly assigned in nearly equal numbers to open-label treatment with bevacizumab alone or bevacizumab plus irinotecan.

Updated results were based on data cutoffs of July 2008 (treatment exposure, safety, and median survival) and July 2009 (survival rates), according to Dr. Cloughesy. The 167 enrolled patients had a median age of about 55 years. The majority were male (68%) and white (90%), and experiencing a first relapse (81%). Progression occurred in 59% of the patients in the bevacizumab arm, and these patients went on to receive the combination therapy.

The median number of bevacizumab doses received was 9 in the bevacizumab group and 11 in the bevacizumab-irinotecan group during the main phase of the trial, reported Dr. Cloughesy, director of the neuro-oncology program and a clinical professor at the Ronald Reagan UCLA Medical Center in Los Angeles. The median number was three during the post-progression phase.

The updated safety data showed little change from the initial results, he said. Some 51% of patients in the bevacizumab group and 71% in the bevacizumab-irinotecan group had adverse events of grade 3 or higher. Hypertension was the predominant event with monotherapy (11%), whereas venous thromboembolism was the predominant event with combination therapy (10%).

“The things that… we are concerned about with regard to patients who are taking anti-VEGF [vascular endothelial growth factor] therapy—cerebral hemorrhage, wound healing, arterial thrombotic embolism, and gastrointestinal perforation—these all stayed fairly low,” he commented. These events occurred at a severity of grade 3 or higher in only 0%-3.6% of patients.

Median overall survival was 9.3 months with bevacizumab alone and 8.9 months with both drugs. The proportion of patients still alive was 38% in each arm at 12 months; 24% and 18%, respectively, at 18 months; 16% and 17%, at 24 months; and 11% and 16%, at 30 months.

Dr. Alba A. Brandes, a medical oncologist at Azienda USL in Bologna, Italy, noted that the trial's size and promising results were strengths, but said its evaluation criteria and lack of a standard control arm and biomarker studies were weaknesses.

“Bevacizumab has brought light into the treatment of recurrent GBM, a setting with scarce options and dismal results,” she commented. “The advantage of bevacizumab over classical cytotoxics seems to be in the range of 2 to 3 months. That represents a prolongation of 30% in survival at recurrence,” said Dr. Brandes. “However, this advantage should be proven in phase III trials.”

We think the majority of the effect that we are seeing with the two drugs in this trial comes from bevacizumab.

Source DR. CLOUGHESY

Major Finding: The 12-month rate of survival was 38% with both bevacizumab alone and bevacizumab plus irinotecan in updated analyses, and no new adverse effects were noted.

Data Source: A randomized, noncomparative, open-label phase II trial among 167 patients with relapsed glioblastoma multiforme (the BRAIN trial).

Disclosures: Genentech sponsored the trial. Some of the investigators are employees of or consultants to Genentech, or have received honoraria or research funding from the company. Dr. Brandes disclosed having a consultant or advisory role with and receiving honoraria from Roche, which owns Genentech.

CHICAGO — Bevacizumab, alone or in combination with irinotecan, is generally safe and active in patients with relapsed glioblastoma, according to updated results of the phase II BRAIN trial.

“Up to 16% of patients who received bevacizumab-based therapy remained alive at 30 months,” lead investigator Dr. Timothy Cloughesy reported. “The incidence of selected [adverse events] in the updated safety data was consistent with what was previously reported—there were no new safety signals that were identified.”

The Study to Evaluate Bevacizumab Alone or in Combination With Irinotecan for Treatment of Glioblastoma Multiforme (BRAIN) trial's efficacy results compare favorably with those of similar trials testing other regimens, Dr. Cloughesy said: the 12-month survival rate was 38% whereas it has been 14%-27% with cytotoxic agents such as temozolomide (Temo-dar) or lomustine (CCNU).

Sorting out the specific contributions of bevacizumab (Avastin) and irinotecan (Camptosar) to the observed outcomes is difficult because of the trial's design, he said. However, “when we look at what is providing the majority of the effect that we are seeing, I think it is coming from bevacizumab.”

The multicenter trial, sponsored by Genentech (manufacturer of bevacizumab), opened in July 2006 to patients with glioblastoma in first or second relapse who had previously received radiation therapy and temozolomide.

They were randomly assigned in nearly equal numbers to open-label treatment with bevacizumab alone or bevacizumab plus irinotecan.

Updated results were based on data cutoffs of July 2008 (treatment exposure, safety, and median survival) and July 2009 (survival rates), according to Dr. Cloughesy. The 167 enrolled patients had a median age of about 55 years. The majority were male (68%) and white (90%), and experiencing a first relapse (81%). Progression occurred in 59% of the patients in the bevacizumab arm, and these patients went on to receive the combination therapy.

The median number of bevacizumab doses received was 9 in the bevacizumab group and 11 in the bevacizumab-irinotecan group during the main phase of the trial, reported Dr. Cloughesy, director of the neuro-oncology program and a clinical professor at the Ronald Reagan UCLA Medical Center in Los Angeles. The median number was three during the post-progression phase.

The updated safety data showed little change from the initial results, he said. Some 51% of patients in the bevacizumab group and 71% in the bevacizumab-irinotecan group had adverse events of grade 3 or higher. Hypertension was the predominant event with monotherapy (11%), whereas venous thromboembolism was the predominant event with combination therapy (10%).

“The things that… we are concerned about with regard to patients who are taking anti-VEGF [vascular endothelial growth factor] therapy—cerebral hemorrhage, wound healing, arterial thrombotic embolism, and gastrointestinal perforation—these all stayed fairly low,” he commented. These events occurred at a severity of grade 3 or higher in only 0%-3.6% of patients.

Median overall survival was 9.3 months with bevacizumab alone and 8.9 months with both drugs. The proportion of patients still alive was 38% in each arm at 12 months; 24% and 18%, respectively, at 18 months; 16% and 17%, at 24 months; and 11% and 16%, at 30 months.

Dr. Alba A. Brandes, a medical oncologist at Azienda USL in Bologna, Italy, noted that the trial's size and promising results were strengths, but said its evaluation criteria and lack of a standard control arm and biomarker studies were weaknesses.

“Bevacizumab has brought light into the treatment of recurrent GBM, a setting with scarce options and dismal results,” she commented. “The advantage of bevacizumab over classical cytotoxics seems to be in the range of 2 to 3 months. That represents a prolongation of 30% in survival at recurrence,” said Dr. Brandes. “However, this advantage should be proven in phase III trials.”

We think the majority of the effect that we are seeing with the two drugs in this trial comes from bevacizumab.

Source DR. CLOUGHESY

Major Finding: The 12-month rate of survival was 38% with both bevacizumab alone and bevacizumab plus irinotecan in updated analyses, and no new adverse effects were noted.

Data Source: A randomized, noncomparative, open-label phase II trial among 167 patients with relapsed glioblastoma multiforme (the BRAIN trial).

Disclosures: Genentech sponsored the trial. Some of the investigators are employees of or consultants to Genentech, or have received honoraria or research funding from the company. Dr. Brandes disclosed having a consultant or advisory role with and receiving honoraria from Roche, which owns Genentech.

CHICAGO — Bevacizumab, alone or in combination with irinotecan, is generally safe and active in patients with relapsed glioblastoma, according to updated results of the phase II BRAIN trial.

“Up to 16% of patients who received bevacizumab-based therapy remained alive at 30 months,” lead investigator Dr. Timothy Cloughesy reported. “The incidence of selected [adverse events] in the updated safety data was consistent with what was previously reported—there were no new safety signals that were identified.”

The Study to Evaluate Bevacizumab Alone or in Combination With Irinotecan for Treatment of Glioblastoma Multiforme (BRAIN) trial's efficacy results compare favorably with those of similar trials testing other regimens, Dr. Cloughesy said: the 12-month survival rate was 38% whereas it has been 14%-27% with cytotoxic agents such as temozolomide (Temo-dar) or lomustine (CCNU).

Sorting out the specific contributions of bevacizumab (Avastin) and irinotecan (Camptosar) to the observed outcomes is difficult because of the trial's design, he said. However, “when we look at what is providing the majority of the effect that we are seeing, I think it is coming from bevacizumab.”

The multicenter trial, sponsored by Genentech (manufacturer of bevacizumab), opened in July 2006 to patients with glioblastoma in first or second relapse who had previously received radiation therapy and temozolomide.

They were randomly assigned in nearly equal numbers to open-label treatment with bevacizumab alone or bevacizumab plus irinotecan.

Updated results were based on data cutoffs of July 2008 (treatment exposure, safety, and median survival) and July 2009 (survival rates), according to Dr. Cloughesy. The 167 enrolled patients had a median age of about 55 years. The majority were male (68%) and white (90%), and experiencing a first relapse (81%). Progression occurred in 59% of the patients in the bevacizumab arm, and these patients went on to receive the combination therapy.

The median number of bevacizumab doses received was 9 in the bevacizumab group and 11 in the bevacizumab-irinotecan group during the main phase of the trial, reported Dr. Cloughesy, director of the neuro-oncology program and a clinical professor at the Ronald Reagan UCLA Medical Center in Los Angeles. The median number was three during the post-progression phase.

The updated safety data showed little change from the initial results, he said. Some 51% of patients in the bevacizumab group and 71% in the bevacizumab-irinotecan group had adverse events of grade 3 or higher. Hypertension was the predominant event with monotherapy (11%), whereas venous thromboembolism was the predominant event with combination therapy (10%).

“The things that… we are concerned about with regard to patients who are taking anti-VEGF [vascular endothelial growth factor] therapy—cerebral hemorrhage, wound healing, arterial thrombotic embolism, and gastrointestinal perforation—these all stayed fairly low,” he commented. These events occurred at a severity of grade 3 or higher in only 0%-3.6% of patients.

Median overall survival was 9.3 months with bevacizumab alone and 8.9 months with both drugs. The proportion of patients still alive was 38% in each arm at 12 months; 24% and 18%, respectively, at 18 months; 16% and 17%, at 24 months; and 11% and 16%, at 30 months.

Dr. Alba A. Brandes, a medical oncologist at Azienda USL in Bologna, Italy, noted that the trial's size and promising results were strengths, but said its evaluation criteria and lack of a standard control arm and biomarker studies were weaknesses.

“Bevacizumab has brought light into the treatment of recurrent GBM, a setting with scarce options and dismal results,” she commented. “The advantage of bevacizumab over classical cytotoxics seems to be in the range of 2 to 3 months. That represents a prolongation of 30% in survival at recurrence,” said Dr. Brandes. “However, this advantage should be proven in phase III trials.”

We think the majority of the effect that we are seeing with the two drugs in this trial comes from bevacizumab.

Source DR. CLOUGHESY

Major Finding: For newly diagnosed GBM patients, median overall survival reached 21.2 months with a regimen incorporating bevacizumab, temozolomide, irinotecan, and radiation.

Data Source: First 75 patients treated with bevacizumab, temozolomide, and radiation followed by bevacizumab, temozolomide, and irinotecan in a phase II trial.

Disclosures: The investigator-sponsored study received support from Genentech Inc. and Schering-Plough. Dr. Vredenburgh said he consults for Genentech.

CHICAGO — A new protocol that adds temozolomide and radiation to bevacizumab and irinotecan for patients with newly diagnosed glioblastoma multiforme has resulted in median overall survival reaching 21.2 months, according to investigators from Duke University.

At 16 months, 65.3% of the first 75 patients in the up-front, phase II trial were still alive, they reported. The 2-year overall survival rate was 45%.

“We were not surprised by the findings. … We had shown that bevacizumab plus irinotecan had good efficacy in glioblastoma,” said principal investigator Dr. James Vredenburgh, a professor of medicine and the medical director of adult clinical services at Duke University Medical Center.

He suggested that the findings will encourage investigators to enroll patients in phase III studies now underway. “I think the phase III studies will change clinical practice,” Dr. Vredenburgh said.

In May 2009, the Food and Drug Administration approved bevacizumab (Avastin) mono-therapy second-line for treatment of glioblastoma that had progressed after first-line treatment. Temozolomide (Temo-dar) was approved in March 2005 as a first-line treatment with radiation and as a maintenance therapy.

The new experimental protocol uses bevacizumab in combination with temozolomide and radiation therapy, followed by bevacizumab, temozolomide, and irinotecan (Camptosar) for newly diagnosed glioblastoma multiforme and gliosarcoma.

The study rationale was that VEGF (vascular endothelial growth factor) is an essential part of glioblastoma biology, and the anti-VEGF monoclonal antibody bevacizumab has demonstrated synergy with radiation and chemotherapy. Irinotecan was thought possibly to have synergy with temozolomide. Bevacizumab with or without irinotecan had shown activity in recurrent disease, and it was thought that using bevacizumab with chemotherapy in newly diagnosed patients might improve survival.

Using previously reported median survival of 15.8 months in resected patients (N. Engl. J. Med. 2005;352:987-96) as a benchmark, the investigators set the primary end point of this trial as the proportion of patients who were alive 16 months after initiation of combination chemoradiotherapy, with a target of more than 60%.

The study was opened on August 15, 2007, and 75 patients were accrued through September 4, 2008, with a median follow-up of 25 months (range, 19–31 months). A second cohort of 50 patients was enrolled from October 30, 2008, to March 26, 2009. These 50 patients are included in the toxicity data, but not in the survival analysis.

The protocol called for all patients to start receiving radiation therapy and temozolomide at 75 mg/m

After radiation therapy, patients received 6-12 monthly cycles of temozolomide at 200 mg/m

Median progression-free survival reached 14.2 months, and the 2-year progression-free survival rate was 13.3% for the first 75 patients, Dr. Vredenburgh reported.

Median overall survival from progression, which was measured in 62 patients, was 5 months; the 2-year overall survival from progression was 8.8%.

Grade 4 hematologic toxicity occurred in 17 of 125 patients, and deep vein thrombosis/pulmonary embolism occurred in 9 patients.

All other toxicities occurred in not more than two patients. There were four toxic deaths (one each from myocardial infarction, DVT/PE, sepsis, and pneumocystis pneumonia).

Findings should encourage patient enrollment in potentially practice-changing phase III trials.

Source DR. VREDENBURGH

Major Finding: For newly diagnosed GBM patients, median overall survival reached 21.2 months with a regimen incorporating bevacizumab, temozolomide, irinotecan, and radiation.

Data Source: First 75 patients treated with bevacizumab, temozolomide, and radiation followed by bevacizumab, temozolomide, and irinotecan in a phase II trial.

Disclosures: The investigator-sponsored study received support from Genentech Inc. and Schering-Plough. Dr. Vredenburgh said he consults for Genentech.

CHICAGO — A new protocol that adds temozolomide and radiation to bevacizumab and irinotecan for patients with newly diagnosed glioblastoma multiforme has resulted in median overall survival reaching 21.2 months, according to investigators from Duke University.

At 16 months, 65.3% of the first 75 patients in the up-front, phase II trial were still alive, they reported. The 2-year overall survival rate was 45%.

“We were not surprised by the findings. … We had shown that bevacizumab plus irinotecan had good efficacy in glioblastoma,” said principal investigator Dr. James Vredenburgh, a professor of medicine and the medical director of adult clinical services at Duke University Medical Center.

He suggested that the findings will encourage investigators to enroll patients in phase III studies now underway. “I think the phase III studies will change clinical practice,” Dr. Vredenburgh said.

In May 2009, the Food and Drug Administration approved bevacizumab (Avastin) mono-therapy second-line for treatment of glioblastoma that had progressed after first-line treatment. Temozolomide (Temo-dar) was approved in March 2005 as a first-line treatment with radiation and as a maintenance therapy.

The new experimental protocol uses bevacizumab in combination with temozolomide and radiation therapy, followed by bevacizumab, temozolomide, and irinotecan (Camptosar) for newly diagnosed glioblastoma multiforme and gliosarcoma.

The study rationale was that VEGF (vascular endothelial growth factor) is an essential part of glioblastoma biology, and the anti-VEGF monoclonal antibody bevacizumab has demonstrated synergy with radiation and chemotherapy. Irinotecan was thought possibly to have synergy with temozolomide. Bevacizumab with or without irinotecan had shown activity in recurrent disease, and it was thought that using bevacizumab with chemotherapy in newly diagnosed patients might improve survival.

Using previously reported median survival of 15.8 months in resected patients (N. Engl. J. Med. 2005;352:987-96) as a benchmark, the investigators set the primary end point of this trial as the proportion of patients who were alive 16 months after initiation of combination chemoradiotherapy, with a target of more than 60%.

The study was opened on August 15, 2007, and 75 patients were accrued through September 4, 2008, with a median follow-up of 25 months (range, 19–31 months). A second cohort of 50 patients was enrolled from October 30, 2008, to March 26, 2009. These 50 patients are included in the toxicity data, but not in the survival analysis.

The protocol called for all patients to start receiving radiation therapy and temozolomide at 75 mg/m

After radiation therapy, patients received 6-12 monthly cycles of temozolomide at 200 mg/m

Median progression-free survival reached 14.2 months, and the 2-year progression-free survival rate was 13.3% for the first 75 patients, Dr. Vredenburgh reported.

Median overall survival from progression, which was measured in 62 patients, was 5 months; the 2-year overall survival from progression was 8.8%.

Grade 4 hematologic toxicity occurred in 17 of 125 patients, and deep vein thrombosis/pulmonary embolism occurred in 9 patients.

All other toxicities occurred in not more than two patients. There were four toxic deaths (one each from myocardial infarction, DVT/PE, sepsis, and pneumocystis pneumonia).

Findings should encourage patient enrollment in potentially practice-changing phase III trials.

Source DR. VREDENBURGH

Major Finding: For newly diagnosed GBM patients, median overall survival reached 21.2 months with a regimen incorporating bevacizumab, temozolomide, irinotecan, and radiation.

Data Source: First 75 patients treated with bevacizumab, temozolomide, and radiation followed by bevacizumab, temozolomide, and irinotecan in a phase II trial.

Disclosures: The investigator-sponsored study received support from Genentech Inc. and Schering-Plough. Dr. Vredenburgh said he consults for Genentech.

CHICAGO — A new protocol that adds temozolomide and radiation to bevacizumab and irinotecan for patients with newly diagnosed glioblastoma multiforme has resulted in median overall survival reaching 21.2 months, according to investigators from Duke University.

At 16 months, 65.3% of the first 75 patients in the up-front, phase II trial were still alive, they reported. The 2-year overall survival rate was 45%.

“We were not surprised by the findings. … We had shown that bevacizumab plus irinotecan had good efficacy in glioblastoma,” said principal investigator Dr. James Vredenburgh, a professor of medicine and the medical director of adult clinical services at Duke University Medical Center.

He suggested that the findings will encourage investigators to enroll patients in phase III studies now underway. “I think the phase III studies will change clinical practice,” Dr. Vredenburgh said.

In May 2009, the Food and Drug Administration approved bevacizumab (Avastin) mono-therapy second-line for treatment of glioblastoma that had progressed after first-line treatment. Temozolomide (Temo-dar) was approved in March 2005 as a first-line treatment with radiation and as a maintenance therapy.

The new experimental protocol uses bevacizumab in combination with temozolomide and radiation therapy, followed by bevacizumab, temozolomide, and irinotecan (Camptosar) for newly diagnosed glioblastoma multiforme and gliosarcoma.

The study rationale was that VEGF (vascular endothelial growth factor) is an essential part of glioblastoma biology, and the anti-VEGF monoclonal antibody bevacizumab has demonstrated synergy with radiation and chemotherapy. Irinotecan was thought possibly to have synergy with temozolomide. Bevacizumab with or without irinotecan had shown activity in recurrent disease, and it was thought that using bevacizumab with chemotherapy in newly diagnosed patients might improve survival.

Using previously reported median survival of 15.8 months in resected patients (N. Engl. J. Med. 2005;352:987-96) as a benchmark, the investigators set the primary end point of this trial as the proportion of patients who were alive 16 months after initiation of combination chemoradiotherapy, with a target of more than 60%.

The study was opened on August 15, 2007, and 75 patients were accrued through September 4, 2008, with a median follow-up of 25 months (range, 19–31 months). A second cohort of 50 patients was enrolled from October 30, 2008, to March 26, 2009. These 50 patients are included in the toxicity data, but not in the survival analysis.

The protocol called for all patients to start receiving radiation therapy and temozolomide at 75 mg/m

After radiation therapy, patients received 6-12 monthly cycles of temozolomide at 200 mg/m

Median progression-free survival reached 14.2 months, and the 2-year progression-free survival rate was 13.3% for the first 75 patients, Dr. Vredenburgh reported.

Median overall survival from progression, which was measured in 62 patients, was 5 months; the 2-year overall survival from progression was 8.8%.

Grade 4 hematologic toxicity occurred in 17 of 125 patients, and deep vein thrombosis/pulmonary embolism occurred in 9 patients.

All other toxicities occurred in not more than two patients. There were four toxic deaths (one each from myocardial infarction, DVT/PE, sepsis, and pneumocystis pneumonia).

Findings should encourage patient enrollment in potentially practice-changing phase III trials.

Source DR. VREDENBURGH