Outcome of Patients Undergoing Radiotherapy for High Grade Glioma While Taking the Histone Deacetylase Inhibitor, Valproic Acid

Article Outline

• Purpose/Objective(s)
• Materials/Methods
• Results
• Conclusions
• Copyright

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Purpose/Objective(s) 

In preclinical studies, histone deacetylase (HDAC) inhibitors have demonstrated radiosensitizing capabilities. However, no clinical data exists to support the use of HDAC inhibitors with radiotherapy (RT). Valproic acid (VA) is an HDAC inhibitor sometimes used to prevent or treat seizures in patients with CNS neoplasms. The purpose of this study was to assess the outcome of patients using VA during RT for high grade gliomas.

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Materials/Methods 

Institutional databases at Memorial Sloan-Kettering Cancer Center were queried for patients with a diagnosis of a high grade glioma (anaplastic astrocytoma [AA] or glioblastoma multiforme [GBM]), who underwent external beam RT and had pharmacy or laboratory data indicating VA use prior to the end of RT. Clinical records were reviewed to confirm that patients were using VA during RT. Patient clinical data, including the factors (RTOG RPA) prognostic for survival (age, KPS, histology, mental status, extent of surgery, neurologic functional class, RT dose, and duration of symptoms), as well as history of seizures was noted. Concurrent chemotherapy with temozolomide (TMZ) was noted. Any toxicity greater than CTCAE Grade 2 was recorded. Survival of each patient was compared to the median survival of the corresponding RPA class (I-VI).

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Results 

Between 1992 and 2007, 39 patients were identified that were taking VA during RT. Median age was 53 (range, 25-80). Median KPS was 80% (range, 40-100%). Thirty patients had GBM, and 9 had AA. Mental status was normal in 27, abnormal in 12. Six patients underwent biopsy alone, 21 underwent subtotal resection, and 12 underwent gross total resection. Median RT dose was 59.4 Gy (range, 26-68.4 Gy). Seizures were documented in 82% of patients. Concurrent TMZ was used by 36% of patients. No toxicity greater than Grade 2 was noted. Median survival was 16.5 months (range, 1.4-140.6 months), with 31% of patients alive at the time of analysis. The RPA classification by group was: I-6, II-0, III-4, IV-13, V-13, VI-3. When compared to the median survival of patients in their RPA class, 62% of patients exceeded median survival. Subset analyses revealed that 73% of all patients with GBM exceeded RPA class median survival, and that among those patients with GBM treated with RT alone (without TMZ), 76% exceeded median RPA class survival.

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Conclusions 

Patients taking VA during external beam RT appear to have favorable outcomes when compared to historical controls in their RPA class, without experiencing untoward toxicity during treatment. This data provides support to studying VA, or other HDAC inhibitors, in conjunction with RT in an ongoing prospective clinical trial (NCI-06-C-0112).