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EGFR overexpression and radiation response in glioblastoma multiforme
202
I. J. Radiation
180
Oncology
EGFR overexpression
F. G. Barker,‘.’ K. D. Aldape’.
M. L. Simmons,*
‘Massachusetts
General
l Biology
and radiation S. C. Chang,’
l Physics
Volume 48, Number 3, Supplement,
2000
response in glioblastoma
multiforme
M.D.
P. Sneed,’ D. Larson,2 M. S. Berger,’
Prados,’
Hospital, Boston, MA, ‘University
W. Wara,
P. Chen,’
ofCalifornia, San Francisco, San Francisco, CA
Background. Recent comparative genomic hybridization studies have suggested relative radioresistance in glioblastoma multiforme (GM) tumors that harbor extra copies of chromosome 7 sequences. Gene amplification of the epidermal growth factor receptor (EGFR) gene, often in a mutated form, is a frequent event in GM; EGFR is located on chromosome 7p. We hypothesized that EGFR immunopositivity might be associated with relative clinical radioresistance in human GMs. Methods. We studied radiographically-assessed radiation response (5 level scale) in relation to EGFR and ~53 immunoreactivity in a cohort of 130 GM patients treated with external beam radiation using two prospective clinical protocols. Spearman rank correlation and a proportional odds ordinal regression model were used for univariate and multivariate analysis. Results. Immunoreactivity for EGFR was a predictor of poor radiation response (P < 0.05). 33% of 79 tumors with no EGFR immunoreactivity had good radiation responses (>50% reduction in tumor size by CT or MRI), compared to 22% of 22 tumors with weak EGFR staining and 16% of 23 tumors with strong staining. There was no relationship between ~53 immunoreactivity and radiation response. Conclusions.
18
1
The observed
relative radioresistance
In vitro radiosensitivity radiosurgery
of some GMs may be due to abnormalities
of skin fibroblasts
S. C. Malone, J. Szanto, G. Alsbeih, L. Souhami,
predicts for late neurologic
E. Szumacher,
in EGFR expression.
complications
following
AVM
A. Girard, R. Gray, P. Raaphorst
Ottawa Regional Cancer Centre, Ottawa, ON, Canada Purpose: Radiosurgery (RS) is an effective treatment for arteriovenous malformations (AVM) with a low risk of symptomatic brain necrosis. A preliminary study from our institution reported possible genetic differences in radiosensitivity as a potential risk factor for radiation necrosis. This report expands on these findings. Methods: 5 patients (AVM l-5) suffering late radiation necrosis following RS were identified from 3 RS Treatment Centers. Fibroblast cultures were established from skin biopsies. After 5 weeks there was outgrowth of fibroblasts allowing for trypsinization and subculturing. Test cells were irradiated in plateau phase by graded doses (l-8 Gy). Cells were then trypsinized and seeded and after 2 weeks colonies were counted. Survival data from the experiments were pooled and fitted to the linear-quadratic model. The survival fraction at 2 Gy (SF2) of each cell line was derived from experimental data and from the whole survival curves. The SF2 results were compared to the following patient groups: 1) 2 patients with AVMs (AVM 6 & 7) treated with RS and not suffering late sequelae 2) 7 cancer patients treated with radical radiotherapy without late side effects (NS Group) 3) 5 cancer patients (HS Group) suffering severe late radiation sequelae. Results: Clinical and RS data for the 7 AVM patients is given in Table 1 Management of RS necroses included long-term steroids, surgery (1 pt) and hyperbaric oxygen therapy (3 pts). The SF2 values of the 4 patient groups are given in Table 1 The plating efficiency was similar in the cells derived from the 4 patient groups. The SF2’s of the 5 AVM patients suffering necroses were comparable to the HS group but significantly lower than the NS group (p < 0.01). The two AVM control patients had SF2’s in the range seen in the NS group. Conclusions: All 5 patients suffering necrosis following AVM radiosurgery demonstrate enhanced radiosensitivity of normal tissue fibroblast cells in vitro. This study lends strong support to a common genetic predisposition for radiation sensitivity of normal tissues targeted by late radiotoxicity. SF2 of fibroblasts may be useful as a predictive assay to detect patients at risk for RS toxicitv and could allow tailoring of RS doses or to chose alternate therapies in hvpersensitive patients. Patient Group AVM AVM AVM AVM AVM AVM AVM
25 25 15 40 25 25 20
1 2 3 4 5 6 7
NS Group (7 patients) HS Group (5 patients)
182
AVM Size mm mm mm mm mm mm mm
N/A N/A
AVM Locatmn
RS Dose
SF2
Thalamus Occipital corpus Callosum Thalamus Occipital Occipital Occipital N/A N/A
20 Gy 18 Gy 20 Gy 16 Gy 15 Gy 20 Gy 20 Gy N/A N/A
0.18 0.16 0.20 0.17 0.23 0.5 I 0.41 (0.26 to 0.46) (0.10 to 0.21)
Mature phase II results suggest a survival benefit of RSR13 combined in patients with newly diagnosed glioblastoma multiforme
L. R. Kleinberg,’ S. A. Grossman,’ K. Carson,’ Gerber,’ for the NABn CNS Consortium’
G. Lesser,* A. O’Neill,’
J. Pearlman,
with standard
P. Phillips,’
cranial radiotherapy
T. Herman,6 M.
‘Johns Hopkins, Baltimore, MD, ‘Wake Forest, Winston-Salem, NC, -7University of Alabama, Birmingham, AL, ‘H. Lee Mofitt Cancer Center, Tampa, FL, ‘University of Pennsylvania, Philadelphia, PA, ‘Urriversity of Texas, San Antonio, TX, ‘Allos Therapeutics, Inc., Denver, CO, 8New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, MD Purpose/Objective: To determine survival, safety, pharmacodynamics (PD) and pharmacokinetics of RSR13 100 mg/kg per day combined with standard cranial radiotherapy (RT) in the treatment of glioblastoma multiforme (GBM). RSRI 3, an allosteric
I. J. Radiation
180
Oncology
EGFR overexpression
F. G. Barker,‘.’ K. D. Aldape’.
M. L. Simmons,*
‘Massachusetts
General
l Biology
and radiation S. C. Chang,’
l Physics
Volume 48, Number 3, Supplement,
2000
response in glioblastoma
multiforme
M.D.
P. Sneed,’ D. Larson,2 M. S. Berger,’
Prados,’
Hospital, Boston, MA, ‘University
W. Wara,
P. Chen,’
ofCalifornia, San Francisco, San Francisco, CA
Background. Recent comparative genomic hybridization studies have suggested relative radioresistance in glioblastoma multiforme (GM) tumors that harbor extra copies of chromosome 7 sequences. Gene amplification of the epidermal growth factor receptor (EGFR) gene, often in a mutated form, is a frequent event in GM; EGFR is located on chromosome 7p. We hypothesized that EGFR immunopositivity might be associated with relative clinical radioresistance in human GMs. Methods. We studied radiographically-assessed radiation response (5 level scale) in relation to EGFR and ~53 immunoreactivity in a cohort of 130 GM patients treated with external beam radiation using two prospective clinical protocols. Spearman rank correlation and a proportional odds ordinal regression model were used for univariate and multivariate analysis. Results. Immunoreactivity for EGFR was a predictor of poor radiation response (P < 0.05). 33% of 79 tumors with no EGFR immunoreactivity had good radiation responses (>50% reduction in tumor size by CT or MRI), compared to 22% of 22 tumors with weak EGFR staining and 16% of 23 tumors with strong staining. There was no relationship between ~53 immunoreactivity and radiation response. Conclusions.
18
1
The observed
relative radioresistance
In vitro radiosensitivity radiosurgery
of some GMs may be due to abnormalities
of skin fibroblasts
S. C. Malone, J. Szanto, G. Alsbeih, L. Souhami,
predicts for late neurologic
E. Szumacher,
in EGFR expression.
complications
following
AVM
A. Girard, R. Gray, P. Raaphorst
Ottawa Regional Cancer Centre, Ottawa, ON, Canada Purpose: Radiosurgery (RS) is an effective treatment for arteriovenous malformations (AVM) with a low risk of symptomatic brain necrosis. A preliminary study from our institution reported possible genetic differences in radiosensitivity as a potential risk factor for radiation necrosis. This report expands on these findings. Methods: 5 patients (AVM l-5) suffering late radiation necrosis following RS were identified from 3 RS Treatment Centers. Fibroblast cultures were established from skin biopsies. After 5 weeks there was outgrowth of fibroblasts allowing for trypsinization and subculturing. Test cells were irradiated in plateau phase by graded doses (l-8 Gy). Cells were then trypsinized and seeded and after 2 weeks colonies were counted. Survival data from the experiments were pooled and fitted to the linear-quadratic model. The survival fraction at 2 Gy (SF2) of each cell line was derived from experimental data and from the whole survival curves. The SF2 results were compared to the following patient groups: 1) 2 patients with AVMs (AVM 6 & 7) treated with RS and not suffering late sequelae 2) 7 cancer patients treated with radical radiotherapy without late side effects (NS Group) 3) 5 cancer patients (HS Group) suffering severe late radiation sequelae. Results: Clinical and RS data for the 7 AVM patients is given in Table 1 Management of RS necroses included long-term steroids, surgery (1 pt) and hyperbaric oxygen therapy (3 pts). The SF2 values of the 4 patient groups are given in Table 1 The plating efficiency was similar in the cells derived from the 4 patient groups. The SF2’s of the 5 AVM patients suffering necroses were comparable to the HS group but significantly lower than the NS group (p < 0.01). The two AVM control patients had SF2’s in the range seen in the NS group. Conclusions: All 5 patients suffering necrosis following AVM radiosurgery demonstrate enhanced radiosensitivity of normal tissue fibroblast cells in vitro. This study lends strong support to a common genetic predisposition for radiation sensitivity of normal tissues targeted by late radiotoxicity. SF2 of fibroblasts may be useful as a predictive assay to detect patients at risk for RS toxicitv and could allow tailoring of RS doses or to chose alternate therapies in hvpersensitive patients. Patient Group AVM AVM AVM AVM AVM AVM AVM
25 25 15 40 25 25 20
1 2 3 4 5 6 7
NS Group (7 patients) HS Group (5 patients)
182
AVM Size mm mm mm mm mm mm mm
N/A N/A
AVM Locatmn
RS Dose
SF2
Thalamus Occipital corpus Callosum Thalamus Occipital Occipital Occipital N/A N/A
20 Gy 18 Gy 20 Gy 16 Gy 15 Gy 20 Gy 20 Gy N/A N/A
0.18 0.16 0.20 0.17 0.23 0.5 I 0.41 (0.26 to 0.46) (0.10 to 0.21)
Mature phase II results suggest a survival benefit of RSR13 combined in patients with newly diagnosed glioblastoma multiforme
L. R. Kleinberg,’ S. A. Grossman,’ K. Carson,’ Gerber,’ for the NABn CNS Consortium’
G. Lesser,* A. O’Neill,’
J. Pearlman,
with standard
P. Phillips,’
cranial radiotherapy
T. Herman,6 M.
‘Johns Hopkins, Baltimore, MD, ‘Wake Forest, Winston-Salem, NC, -7University of Alabama, Birmingham, AL, ‘H. Lee Mofitt Cancer Center, Tampa, FL, ‘University of Pennsylvania, Philadelphia, PA, ‘Urriversity of Texas, San Antonio, TX, ‘Allos Therapeutics, Inc., Denver, CO, 8New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, MD Purpose/Objective: To determine survival, safety, pharmacodynamics (PD) and pharmacokinetics of RSR13 100 mg/kg per day combined with standard cranial radiotherapy (RT) in the treatment of glioblastoma multiforme (GBM). RSRI 3, an allosteric