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Analysis of Patients Receiving Histone Deacetylase Inhibiting Antiepileptic Agents during Radiation Treatment for Glioblastoma
I. J. Radiation Oncology d Biology d Physics
S228
Volume 72, Number 1, Supplement, 2008
Conclusions: Adjuvant GKR following resection for patients with limited brain metastases using a median dose of 15 Gy provided excellent local control and survival with minimal toxicity. The omission of upfront WBRT in limited brain metastases patients does not appear to compromise survival or intracranial control, allowing for salvage therapy as indicated. GKR should be further evaluated as an acceptable alternative to WBI after resection of limited brain metastases. Author Disclosure: D. Pieper, None; A.W. Suen, None; I.S. Grills, None; S. Nandalur, None; N. Mohammed, None; C. Mitchell, None; A. Maitz, None; S.N. Kalkanis, None; A.A. Martinez, None; P.Y. Chen, None.
2131
Analysis of Patients Receiving Histone Deacetylase Inhibiting Antiepileptic Agents during Radiation Treatment for Glioblastoma
E. P. Sulman, C. E. Pelloski, K. D. Aldape M.D. Anderson Cancer Center, Houston, TX Purpose/Objective(s): Glioblastoma (GBM) is a devastating disease with a 1 yr median survival. The addition of temozolomide (TMZ) to radiation has led to improved survival, but additional radiosensitizing agents are needed. Current supportive treatment often includes the use of antiepileptic drugs, some of which, such as valproic acid (VA), have been shown to exhibit histone deacetylase (HDAC) inhibitor activity with a potential role in radiation sensitization. We hypothesized that patients with GBM treated with these drugs during the course of their radiotherapy would exhibit improved outcomes. Materials/Methods: Clinical records were examined retrospectively in patients diagnosed with GBM between 1996 and 2006 from our institution. Outcomes included overall survival (OS), progression-free survival (PFS), and radiation response. PFS was determined based on the radiographically apparent tumor progression. RT response was scored based on a comparison of the amount of residual enhancement between the pre- and post-RT MRIs. Initially, the use of VA, for which a pre-clinical role in radiosensitization has been demonstrated, was analyzed separately. Additional antiepileptic agents with known HDAC inhibitory effects were then examined together with valproic acid. Results: Data for 269 patients were available for analysis with a median age of 58 y. Median OS and PFS for the cohort were 62 weeks and 20 weeks, respectively. RT response ranging from stable enhancement to a .50% decrease in the size of enhancement among subtotally resected patients was seen in 115 (43%) of cases. Concurrent TMZ was given to 142 patients (53%). Sixteen patients (6%) received VA during the course of their treatment. Other antiepileptic agents were given in 175 cases and included phenytoin (69%), levetiracetam (19%), and carbamazepine (7%). No significant benefit in OS, PFS, or RT response was seen for patients receiving VA. Median OS and PFS for the VA receiving group was 64 wks and 22 wks, respectively, compared to 63 wks and 19 wks, respectively, for the no-VA group. Eight patients (50%) of the VA group showed a response to RT compared to 107 (44%) in the non-VA group (p = NS). When patients receiving VA were combined with those receiving other HDAC inhibitory antiepileptic drugs (n = 51), the results were similarly not significant for all outcomes. Among the subset of patients receive TMZ, HDAC inhibitors resulted in a modest, but not statistically significant improvement in median OS (62 wks vs. 48 wks, p = 0.18), but no difference in PFS or RT response. Conclusions: The use of antiepileptic, HDAC inhibiting drugs during radiotherapy for GBM did not improve outcome in this retrospective analysis. While potentially beneficial, further study is needed to determine a benefit for the combination of TMZ and HDAC inhibitors. Author Disclosure: E.P. Sulman, None; C.E. Pelloski, None; K.D. Aldape, None.
2132
Hypofractionated IMRT for Large, Difficult Brain Metastases
K. P. Beal, Y. Yamada, T. A. Chan, Z. Zhang, W. Shi, J. Cruz, C. Brennan, V. Tabar, P. H. Gutin Memorial Sloan-Kettering Cancer Center, New York, NY Purpose/Objective(s): To review our experience with hypofractionated IMRT partial brain radiotherapy (PBRT) for metastases. Materials/Methods: Between 10/2001 and 10/2007 41 patients (43 lesions) were treated with 5 fractions of 600cGy over 2.5 weeks to partial brain with IMRT for metastases. The median size of the GTV (or CTV for post-operative cavities) was 2.8 cm (range, 0.5-6.0 cm) and a 0.5 cm margin was added to create a PTV. Patients were treated after a gross-total (11) or sub-total resection (1), biopsy (15), or based on radiographic findings (16) if they had confirmed metastatic disease elsewhere. Primary pathology included: NSCLCA (12), breast cancer (9), renal cell carcinoma (7), melanoma (6), soft tissue sarcoma (2), ovarian cancer (2), colorectal cancer (2), SCLCA (1), testicular carcinoma (1), and papillary thyroid cancer (1). Twelve patients had received prior brain radiation including: stereotactic radiosurgery (SRS) (5), whole brain radiation therapy (WBRT) (3), SRS and WBRT (1), PBRT to the same location (2), and PBRT to a different location (1). Sites of treatment were: supratentorial (28), posterior fossa (4), brainstem (4), ventricular (4), and dural (3). Results: PBRT was well tolerated with minimal to no acute side effects. Median follow-up was 8 months (range, 1-41 mo). The median overall survival (OS) was 13 months (95%CI, 10 mo - not reached). The 1 year OS was 59% (95% CI, 0.39 - 0.74). Patients were followed with MRIs every 2 months. Local control of the target lesion was 72% (95%CI, 0.5-0.85) at 1 year and freedom from progression elsewhere in the brain was 59% (95%CI, 0.4-0.75) at 1 year. The 2 patients that had received prior SRS to the same site developed necrosis that required surgical intervention. No other cases of necrosis were observed. Nine of the treated lesions (21%) developed in field recurrence. Thirteen (30%) of the treated lesions developed recurrence elsewhere in the brain and 7 received subsequent radiation including WBRT (2), SRS (2), and PBRT (3). Log-rank test demonstrated that a larger lesion (.3 vs. #3 cm) was a significant predictor for target recurrence (p = 0.04). Other variables tested included prior radiation, target lesion size (continuous), and surgery type. A multivariate Cox regression analysis revealed a trend in which a lesion .3cm was more likely associated with target recurrence in the brain (p = 0.06). Conclusions: PBRT is safe, effective, and well tolerated. The local control rate is high for this group that includes even classically radioresistant histologies. The necrosis rate was low occurring only in patients who had received prior SRS to the same site.
S228
Volume 72, Number 1, Supplement, 2008
Conclusions: Adjuvant GKR following resection for patients with limited brain metastases using a median dose of 15 Gy provided excellent local control and survival with minimal toxicity. The omission of upfront WBRT in limited brain metastases patients does not appear to compromise survival or intracranial control, allowing for salvage therapy as indicated. GKR should be further evaluated as an acceptable alternative to WBI after resection of limited brain metastases. Author Disclosure: D. Pieper, None; A.W. Suen, None; I.S. Grills, None; S. Nandalur, None; N. Mohammed, None; C. Mitchell, None; A. Maitz, None; S.N. Kalkanis, None; A.A. Martinez, None; P.Y. Chen, None.
2131
Analysis of Patients Receiving Histone Deacetylase Inhibiting Antiepileptic Agents during Radiation Treatment for Glioblastoma
E. P. Sulman, C. E. Pelloski, K. D. Aldape M.D. Anderson Cancer Center, Houston, TX Purpose/Objective(s): Glioblastoma (GBM) is a devastating disease with a 1 yr median survival. The addition of temozolomide (TMZ) to radiation has led to improved survival, but additional radiosensitizing agents are needed. Current supportive treatment often includes the use of antiepileptic drugs, some of which, such as valproic acid (VA), have been shown to exhibit histone deacetylase (HDAC) inhibitor activity with a potential role in radiation sensitization. We hypothesized that patients with GBM treated with these drugs during the course of their radiotherapy would exhibit improved outcomes. Materials/Methods: Clinical records were examined retrospectively in patients diagnosed with GBM between 1996 and 2006 from our institution. Outcomes included overall survival (OS), progression-free survival (PFS), and radiation response. PFS was determined based on the radiographically apparent tumor progression. RT response was scored based on a comparison of the amount of residual enhancement between the pre- and post-RT MRIs. Initially, the use of VA, for which a pre-clinical role in radiosensitization has been demonstrated, was analyzed separately. Additional antiepileptic agents with known HDAC inhibitory effects were then examined together with valproic acid. Results: Data for 269 patients were available for analysis with a median age of 58 y. Median OS and PFS for the cohort were 62 weeks and 20 weeks, respectively. RT response ranging from stable enhancement to a .50% decrease in the size of enhancement among subtotally resected patients was seen in 115 (43%) of cases. Concurrent TMZ was given to 142 patients (53%). Sixteen patients (6%) received VA during the course of their treatment. Other antiepileptic agents were given in 175 cases and included phenytoin (69%), levetiracetam (19%), and carbamazepine (7%). No significant benefit in OS, PFS, or RT response was seen for patients receiving VA. Median OS and PFS for the VA receiving group was 64 wks and 22 wks, respectively, compared to 63 wks and 19 wks, respectively, for the no-VA group. Eight patients (50%) of the VA group showed a response to RT compared to 107 (44%) in the non-VA group (p = NS). When patients receiving VA were combined with those receiving other HDAC inhibitory antiepileptic drugs (n = 51), the results were similarly not significant for all outcomes. Among the subset of patients receive TMZ, HDAC inhibitors resulted in a modest, but not statistically significant improvement in median OS (62 wks vs. 48 wks, p = 0.18), but no difference in PFS or RT response. Conclusions: The use of antiepileptic, HDAC inhibiting drugs during radiotherapy for GBM did not improve outcome in this retrospective analysis. While potentially beneficial, further study is needed to determine a benefit for the combination of TMZ and HDAC inhibitors. Author Disclosure: E.P. Sulman, None; C.E. Pelloski, None; K.D. Aldape, None.
2132
Hypofractionated IMRT for Large, Difficult Brain Metastases
K. P. Beal, Y. Yamada, T. A. Chan, Z. Zhang, W. Shi, J. Cruz, C. Brennan, V. Tabar, P. H. Gutin Memorial Sloan-Kettering Cancer Center, New York, NY Purpose/Objective(s): To review our experience with hypofractionated IMRT partial brain radiotherapy (PBRT) for metastases. Materials/Methods: Between 10/2001 and 10/2007 41 patients (43 lesions) were treated with 5 fractions of 600cGy over 2.5 weeks to partial brain with IMRT for metastases. The median size of the GTV (or CTV for post-operative cavities) was 2.8 cm (range, 0.5-6.0 cm) and a 0.5 cm margin was added to create a PTV. Patients were treated after a gross-total (11) or sub-total resection (1), biopsy (15), or based on radiographic findings (16) if they had confirmed metastatic disease elsewhere. Primary pathology included: NSCLCA (12), breast cancer (9), renal cell carcinoma (7), melanoma (6), soft tissue sarcoma (2), ovarian cancer (2), colorectal cancer (2), SCLCA (1), testicular carcinoma (1), and papillary thyroid cancer (1). Twelve patients had received prior brain radiation including: stereotactic radiosurgery (SRS) (5), whole brain radiation therapy (WBRT) (3), SRS and WBRT (1), PBRT to the same location (2), and PBRT to a different location (1). Sites of treatment were: supratentorial (28), posterior fossa (4), brainstem (4), ventricular (4), and dural (3). Results: PBRT was well tolerated with minimal to no acute side effects. Median follow-up was 8 months (range, 1-41 mo). The median overall survival (OS) was 13 months (95%CI, 10 mo - not reached). The 1 year OS was 59% (95% CI, 0.39 - 0.74). Patients were followed with MRIs every 2 months. Local control of the target lesion was 72% (95%CI, 0.5-0.85) at 1 year and freedom from progression elsewhere in the brain was 59% (95%CI, 0.4-0.75) at 1 year. The 2 patients that had received prior SRS to the same site developed necrosis that required surgical intervention. No other cases of necrosis were observed. Nine of the treated lesions (21%) developed in field recurrence. Thirteen (30%) of the treated lesions developed recurrence elsewhere in the brain and 7 received subsequent radiation including WBRT (2), SRS (2), and PBRT (3). Log-rank test demonstrated that a larger lesion (.3 vs. #3 cm) was a significant predictor for target recurrence (p = 0.04). Other variables tested included prior radiation, target lesion size (continuous), and surgery type. A multivariate Cox regression analysis revealed a trend in which a lesion .3cm was more likely associated with target recurrence in the brain (p = 0.06). Conclusions: PBRT is safe, effective, and well tolerated. The local control rate is high for this group that includes even classically radioresistant histologies. The necrosis rate was low occurring only in patients who had received prior SRS to the same site.