September 1, 2011 — A new study suggests that use of the antiepileptic drug (AED) valproic acid may improve survival among patients with newly diagnosed glioblastoma receiving temozolomide radiochemotherapy vs other such drugs or no treatment.
Retrospective analysis of the pivotal European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) clinical trial showed those receiving valproic acid with temozolomide radiochemotherapy survived an average of 3 months longer than those taking other enzyme-inducing AEDs or receiving no AED treatment.
This effect wasn’t seen among patients who received radiotherapy alone. Those receiving valproic acid, though, had higher rates of thrombocytopenia, leukopenia, and neutropenia than those taking other or no AEDs.
"Despite the limitations of this retrospective analysis, these results suggest that the choice of AED in patients with brain tumors should be carefully considered because it may affect survival," the authors, led by Michael Weller, MD, from the University Hospital Zurich, Switzerland, conclude.
This observation also further supports a recent trend to favor a non-enzyme-inducing AED for patients with a malignancy to allow administration of modern chemotherapy and targeted agents that often show increased hepatic metabolism if patients are given an enzyme-inducing agent, they add.
The study was published online August 31 in Neurology.
"Thoughtful" Use of Antiepileptic Drugs
Seizures occur in up to 50% of patients with glioblastomas, the researchers report. There are many considerations to the "thoughtful" use of AEDs in these patients, they note, including the resistance of the seizure disorder, drug-to-drug interactions and side effects.
Rash, drowsiness, or other cognitive alterations may affect the patients’ quality of life, they point out, and drug interactions with chemotherapy are a concern because of overlapping hematologic toxicity or hepatic enzyme induction or inhibition.
"Notably, the older AEDs such as phenytoin, phenobarbital, or carbamazepine will induce a number of coenzymes of the cyto-chrome P450 system and may thus enhance the metabolism of many commonly administered chemotherapy agents as well as corticosteroids," the authors write. "Conversely, the enzyme-inhibiting effect of valproic acid appears clinically of lesser importance although increased myelosuppression may develop in patients receiving nitrosoureas or cisplatinum-based chemotherapy concomitantly."
Intrinsic antitumor activity of certain AEDs and synergy with chemotherapy or radiotherapy has been suggested in some, but not all, studies, they point out. For instance, phenytoin has been attributed antimitotic and anti-invasive properties, and valproic acid has been suggested to induce cell differentiation, growth arrest, and apoptosis mediated by its histone deacetylase–inhibiting properties.
A recent retrospective analysis of 3 trials performed by the North Central Cancer Treatment Group and published in 2009 suggested a possible association of enzyme-inducing AED use with a favorable outcome in patients with glioblastoma, Dr. Weller and coauthors write. "This observation prompted us to assess a potential predictive value on outcome of the AED used within the pivotal trial of concomitant and adjuvant temozolomide and radiotherapy, the current standard of care."
The EORTC/NCIC clinical trial database of radiotherapy with or without temozolomide for newly diagnosed glioblastoma was examined to look for the effect of any interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors.
When treatment began, they write, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED, and 135 (23.4%) were taking any non-enzyme-inducing AED.
Patients receiving valproic acid only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an enzyme-inducing AED only, they report.
The overall survival of patients who were receiving an AED at baseline vs those not receiving any AED was similar, the authors note. However, patients receiving valproic acid alone appeared to derive more survival benefit from temozolomide radiochemotherapy than patients receiving only an enzyme-inducing AED, or those not receiving any AED.
Survival With Temozolomide Radiochemotherapy by AED Treatment
CI = confidence interval
Valproic acid may be preferred over an enzyme-inducing AED in patients with glioblastoma who require an AED during temozolomide-based chemoradiotherapy, they conclude. "Future studies are needed to determine whether [valproic acid] increases [temozolomide] bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo."
Jury Still Out?
In an editorial accompanying the paper, Patrick Y. Wen, MD, from the Department of Neurology at Brigham and Women’s Hospital and Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts, and David Schiff, MD, from the University of Virginia Medical Center in Charlottesville, write that although the results are "intriguing," they should still be interpreted with caution until further information becomes available.
First, they point out, as the researchers also do, that the results are from an unplanned retrospective analysis and that the study was underpowered and not randomized.
The finding that median overall survival in the radiation-alone group was worse in patients receiving valproic acid, at 10.1 months, than in those receiving enzyme-inducing AEDs (12.5 months) and those without an AED (12.0 months), they write, "is surprising and raises the possibility that the apparent benefit of [valproic acid] with radiation and temozolomide occurred by chance."
In addition, they note, valproic acid was associated with a higher rate of hematologic toxicity during adjuvant temozolomide therapy and almost twice as many patients required delays in their treatment cycles.
"Fortunately, additional data addressing this issue may be forthcoming from analysis of the recently completed Radiation Therapy Oncology Group phase 3 trial (RTOG 0525) comparing standard adjuvant temozolomide vs a dose-dense regimen, as well as phase 2 trials of [valproic acid]…and the HDAC [histone deacetylase] inhibitor vorinostat…with radiation therapy and temozolomide for newly diagnosed glioblastoma," Dr. Wen and Dr. Schiff conclude.
"Until data from these studies become available, it is unclear whether the potential survival benefit of [valproic acid] outweighs the definite increase in hematologic toxicity."
The study was supported by the National Cancer Institute in the United States and a grant from the Swiss Cancer League to the European Organisation for Research and Treatment of Cancer Charitable Trust in Switzerland. Dr. Weller serves on scientific advisory boards for Roche, Merck Serono, Merck & Co., Inc., OncoMethylome Sciences, Exelixis Inc., and Bristol-Myers Squibb; received funding for travel or speaker honoraria from Roche, Merck Serono, Schering Plough Corp., and Merck & Co., Inc.; serves as European Editor for the Journal of Neuro-Oncology and on the editorial boards of Glia, Journal of Neuro-Oncology, Journal of Neurochemistry, and Cellular Physiology & Biochemistry; and receives research support from Roche, Merck Serono, Schering Plough Corp., and Merck & Co., Inc. Disclosures for other coauthors appear in the article.
Dr. Wen serves on scientific advisory boards for Merck, Genzyme Corp., Eli Lilly and Co., and Novartis; received funding for travel or speaker honoraria from Merck; serves as an Associate Editor for the Journal of Neuro-Oncology; and receives research support from Merck, Genentech, Inc., AstraZeneca, Medimmune, Amgen, VBL Therapeutics, and Novartis. Dr. Schiff served on a scientific advisory boards for Genentech, Inc., VBL Therapeutics, and Merck; serves on the editorial board of Neurology; receives publishing royalties from UpToDate; and serves as a consultant for Tau Therapeutics.
Neurology. 2011;77:1156-1164. Abstract
Retrospective analysis of the pivotal European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) clinical trial showed those receiving valproic acid with temozolomide radiochemotherapy survived an average of 3 months longer than those taking other enzyme-inducing AEDs or receiving no AED treatment.
This effect wasn’t seen among patients who received radiotherapy alone. Those receiving valproic acid, though, had higher rates of thrombocytopenia, leukopenia, and neutropenia than those taking other or no AEDs.
"Despite the limitations of this retrospective analysis, these results suggest that the choice of AED in patients with brain tumors should be carefully considered because it may affect survival," the authors, led by Michael Weller, MD, from the University Hospital Zurich, Switzerland, conclude.
This observation also further supports a recent trend to favor a non-enzyme-inducing AED for patients with a malignancy to allow administration of modern chemotherapy and targeted agents that often show increased hepatic metabolism if patients are given an enzyme-inducing agent, they add.
The study was published online August 31 in Neurology.
"Thoughtful" Use of Antiepileptic Drugs
Seizures occur in up to 50% of patients with glioblastomas, the researchers report. There are many considerations to the "thoughtful" use of AEDs in these patients, they note, including the resistance of the seizure disorder, drug-to-drug interactions and side effects.
Rash, drowsiness, or other cognitive alterations may affect the patients’ quality of life, they point out, and drug interactions with chemotherapy are a concern because of overlapping hematologic toxicity or hepatic enzyme induction or inhibition.
"Notably, the older AEDs such as phenytoin, phenobarbital, or carbamazepine will induce a number of coenzymes of the cyto-chrome P450 system and may thus enhance the metabolism of many commonly administered chemotherapy agents as well as corticosteroids," the authors write. "Conversely, the enzyme-inhibiting effect of valproic acid appears clinically of lesser importance although increased myelosuppression may develop in patients receiving nitrosoureas or cisplatinum-based chemotherapy concomitantly."
Intrinsic antitumor activity of certain AEDs and synergy with chemotherapy or radiotherapy has been suggested in some, but not all, studies, they point out. For instance, phenytoin has been attributed antimitotic and anti-invasive properties, and valproic acid has been suggested to induce cell differentiation, growth arrest, and apoptosis mediated by its histone deacetylase–inhibiting properties.
A recent retrospective analysis of 3 trials performed by the North Central Cancer Treatment Group and published in 2009 suggested a possible association of enzyme-inducing AED use with a favorable outcome in patients with glioblastoma, Dr. Weller and coauthors write. "This observation prompted us to assess a potential predictive value on outcome of the AED used within the pivotal trial of concomitant and adjuvant temozolomide and radiotherapy, the current standard of care."
The EORTC/NCIC clinical trial database of radiotherapy with or without temozolomide for newly diagnosed glioblastoma was examined to look for the effect of any interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors.
When treatment began, they write, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED, and 135 (23.4%) were taking any non-enzyme-inducing AED.
Patients receiving valproic acid only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an enzyme-inducing AED only, they report.
The overall survival of patients who were receiving an AED at baseline vs those not receiving any AED was similar, the authors note. However, patients receiving valproic acid alone appeared to derive more survival benefit from temozolomide radiochemotherapy than patients receiving only an enzyme-inducing AED, or those not receiving any AED.
Survival With Temozolomide Radiochemotherapy by AED Treatment
| AED | Survival, n (%) | Hazard Ratio (95% CI) |
| Valproic acid | 97 (16.9) | 0.39 (0.24 - 0.63) |
| Enzyme-inducing AED | 252 (44) | 0.69 (0.53 – 0.90) |
| No AED | – | 0.67 (0.49 - 0.93) |
Valproic acid may be preferred over an enzyme-inducing AED in patients with glioblastoma who require an AED during temozolomide-based chemoradiotherapy, they conclude. "Future studies are needed to determine whether [valproic acid] increases [temozolomide] bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo."
Jury Still Out?
In an editorial accompanying the paper, Patrick Y. Wen, MD, from the Department of Neurology at Brigham and Women’s Hospital and Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts, and David Schiff, MD, from the University of Virginia Medical Center in Charlottesville, write that although the results are "intriguing," they should still be interpreted with caution until further information becomes available.
First, they point out, as the researchers also do, that the results are from an unplanned retrospective analysis and that the study was underpowered and not randomized.
The finding that median overall survival in the radiation-alone group was worse in patients receiving valproic acid, at 10.1 months, than in those receiving enzyme-inducing AEDs (12.5 months) and those without an AED (12.0 months), they write, "is surprising and raises the possibility that the apparent benefit of [valproic acid] with radiation and temozolomide occurred by chance."
In addition, they note, valproic acid was associated with a higher rate of hematologic toxicity during adjuvant temozolomide therapy and almost twice as many patients required delays in their treatment cycles.
"Fortunately, additional data addressing this issue may be forthcoming from analysis of the recently completed Radiation Therapy Oncology Group phase 3 trial (RTOG 0525) comparing standard adjuvant temozolomide vs a dose-dense regimen, as well as phase 2 trials of [valproic acid]…and the HDAC [histone deacetylase] inhibitor vorinostat…with radiation therapy and temozolomide for newly diagnosed glioblastoma," Dr. Wen and Dr. Schiff conclude.
"Until data from these studies become available, it is unclear whether the potential survival benefit of [valproic acid] outweighs the definite increase in hematologic toxicity."
The study was supported by the National Cancer Institute in the United States and a grant from the Swiss Cancer League to the European Organisation for Research and Treatment of Cancer Charitable Trust in Switzerland. Dr. Weller serves on scientific advisory boards for Roche, Merck Serono, Merck & Co., Inc., OncoMethylome Sciences, Exelixis Inc., and Bristol-Myers Squibb; received funding for travel or speaker honoraria from Roche, Merck Serono, Schering Plough Corp., and Merck & Co., Inc.; serves as European Editor for the Journal of Neuro-Oncology and on the editorial boards of Glia, Journal of Neuro-Oncology, Journal of Neurochemistry, and Cellular Physiology & Biochemistry; and receives research support from Roche, Merck Serono, Schering Plough Corp., and Merck & Co., Inc. Disclosures for other coauthors appear in the article.
Dr. Wen serves on scientific advisory boards for Merck, Genzyme Corp., Eli Lilly and Co., and Novartis; received funding for travel or speaker honoraria from Merck; serves as an Associate Editor for the Journal of Neuro-Oncology; and receives research support from Merck, Genentech, Inc., AstraZeneca, Medimmune, Amgen, VBL Therapeutics, and Novartis. Dr. Schiff served on a scientific advisory boards for Genentech, Inc., VBL Therapeutics, and Merck; serves on the editorial board of Neurology; receives publishing royalties from UpToDate; and serves as a consultant for Tau Therapeutics.
Neurology. 2011;77:1156-1164. Abstract
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