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Reexamining the radiation therapy oncology group (RTOG) recursive partitioning analysis (RPA) for glioblastoma multiforme (GBM) patients
Proceedings of the 45th Annual ASTRO Meeting
19
FISH Analysis of Genetic Markers of Prognosis for High Grade Astrocyotmas Using Tissue Micro-Arrays from RTOG Clinical Trials
D.J. Brat,1,2 W. Seiferheld,2 A. Perry,3,2 E.H. Hammond,4,2 K.J. Murray,5,2 A. Schulsinger,6,2 M.P. Mehta,7,2 W. Curran8,2 1 Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 2Statistics, Radiation Therapy Oncology Group, Philadelphia, PA, 3Pathology, Washington University School of Medicine, St. Louis, MO, 4Pathology, LDS Hospital, Salt Lake City, UT, 5Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, 6Radiation Oncology, SUNY Health Sciences Center, Brooklyn, NY, 7Human Oncology, University of Wisconsin Medical School, Madison, WI, 8Radiation Oncology, Jefferson Medical College, Philadelphia, PA
Purpose/Objective: Survival varies for patients with high grade astrocytomas. Aside from histologic grade, morphologic features do not reliably predict prognosis. Our goal was to determine if genetic losses from chromosomes 1p, 19q, 9p21, or 10q were associated with long or short survival in anaplastic astrocytoma (AA) and glioblastoma (GBM). We performed fluorescence in situ hybridization (FISH) analysis for these loci on tissue micro-arrays containing 106 high grade astrocytomas from Radiation Therapy Oncology Group (RTOG) clinical trials and correlated the findings with patient survival groups. Materials/Methods: Tissue micro-arrays were constructed using formalin-fixed, paraffin-embedded specimens from 18 AAs and 88 GBMs from RTOG protocols 74-01, 79-03, 79-18, 83-02, 90-06, 93-05, 94-04, 96-02, and 98-06. Cases were selected based on short or long survival. For AA, short and long survivals were ⬍2 yrs and ⬎4 yrs, respectively. For GBM, short and long survivals were ⬍6 mos and ⬎18 mos. Dual-color FISH was performed on 5 micron array sections. For chromosomes 1p and 19q, paired probes were directed at 1p32 and 19q13.4. Paired probes for chromosomes 9p21 and 10q were CEP9/9p21(p16) and CEP10/10q23(PTEN). “Deletion” was defined as ⬎50% nuclei with only one fluorescent signal. Survivals were dichotomized into short- or long-term groups and chromosomal markers were defined as present or deleted. Data was analyzed using Fisher’s exact test of association and logistic regression. AAs and GBMs, 1p and 19q deletions, and 9p21 and 10q deletions were analyzed separately and combined (adjusted p⫽0.025). Results: FISH analysis was possible on 65 to 85 tumors per micro-array depending on the marker. Chromosome 1p deletions were noted in 2 (17%) AAs and 0 GBMs, whereas 19q deletions were noted in 3 (20%) AAs and 7 (10%) GBMs. Combined 1p and 19q loss was detected in 2 (13%) AAs and 0 GBMs. Chromosome 9p21 loss was seen in 5 (63%) AAs and 39 (68%) GBMs. Chromosome 10q loss was detected in 4 (27%) AAs and 48 (71%) GBMs. 19q deletions were more frequent in long term than short term survivors for AAs (43% vs. 0%), GBMs (15% vs. 5%), and AA⫹GBM (20% vs. 4%). 10q deletions were more frequent in short term than long term survivors for AAs (38% vs. 14%), GBMs (75% vs. 66%), and AA⫹GBM (68% vs. 56%). 9p21 deletions were slightly more frequent in short term than long term survivors for AAs (67% vs. 60%), GBMs (72% vs. 64%) and AA⫹GBM (72% vs. 64%). No comparisons were statistically significant. Conclusions: We found that losses of chromosome 1p alone and the combined loss of 1p and 19q were rare events in high grade astrocytomas. This contrasts with oligodendrogliomas, in which combined 1p and 19q loss is frequent (60 –70%) and predictive of prolonged survival. The long-term survival group of high-grade astrocytomas showed a trend towards a higher frequency of 19q loss (p⫽0.041). 9p21 and 10q deletions, generally regarded as late events in the progression to GBM, were slightly more frequent in short term survivors. Long and short-term survival groups of high-grade astrocytomas may have dissimilar frequencies of 19q, 9p21, and 10q deletions. A study of overall patient survival with these genetic markers could address prognostic significance more definitively.
20
Reexamining the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) for Glioblastoma Multiforme (GBM) Patients
E.G. Shaw,1 W. Seiferheld,2 C. Scott,2 C. Coughlin,5 S. Leibel,3 W. Curran,4 M. Mehta6 1 Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, 2Statistics, RTOG, Philadelphia, PA, 3Radiation Oncology, Duke University Medical Center, Durham, NC, 4Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, 5Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, 6Human Oncology, University of Wisconsin Hospital/Medical School, Madison, WI
Purpose/Objective: To determine whether the original RPA classification of malignant glioma patients (pts) could be improved upon by restricting the model to GBM pts, considering additional/different baseline variables, and by adding newer studies to the RTOG malignant glioma database. Materials/Methods: The new RPA considered 42 baseline variables and included 1672 GBM pts, compared to 32 variables and 1288 GBM pts (plus 290 AA) included in the original analysis. In the new analysis, radiation dose assigned rather than radiation dose received was used as the radiation treatment variable. The new analysis included two additional studies (RTOG 90-06 and 94-11), and excluded radiation treatment (RT) alone arms from the original database, such that all patients received BCNU plus RT. In order to compare the models, they were applied to a “test set” of 488 pts on six Phase II RTOG studies (76-11, 79-03, 80-07, 84-09, 95-13, 96-02), and evaluated by calculating explained variation (squared error loss), and determining whether the RPA classes provided statistically significantly distinct survival groups. Results: The original model explained more statistical variation than the new model in the test set of RTOG studies. However, RPA classes V and VI from the original model were not statistically significantly different when applied to the test set of studies, i.e., the variables mental status and radiation dose are no longer required. Therefore, we chose a simplified version of the original RPA model by combining classes V and VI, which results in three classes with statistically significantly distinct survival. This simplified model is easier to apply, since it involves only four variables: age, KPS, extent of resection (gross total or subtotal resection (G/STR) vs biopsy), and neurologic function (working (W⫹) or not working (W⫺)). Applying this simpler version of the original RPA model to the updated glioma database provided the results shown in the table and figure below.
S135
S136
I. J. Radiation Oncology
● Biology ● Physics
Volume 57, Number 2, Supplement, 2003
Conclusions: A simplified version of the original RPA model for only GBM patients combines RPA classes V and VI and results in three distinct prognostic groups defined by age, performance status, extent of resection, and neurologic function. The RTOG will use this simplified RPA classification in future clinical trials.
21
Gamma Knife Radiosurgery for Treatment of Trigeminal Neuralgia
V. Mehta,1,2 R. Meier,1,2 J. Gilrein,2 S. Vermeulen,1,2 R. Young2 1 Radiation Oncology, Swedish Cancer Institute, Seattle, WA, 2Northwest Gamma Knife Center, Swedish Cancer Institute, Seattle, WA
Purpose/Objective: We investigated the clinical outcomes in patients treated with gamma knife radiosurgery for trigeminal neuralgia. Materials/Methods: Two hundred fifty patients with trigeminal neuralgia were treated with gamma knife radiosurgery. One hundred fifteen patients had undergone a prior surgical procedure. None of the patients had multiple sclerosis or tumor associated trigeminal neuralgia. The median patient age was 62. Patients were treated on three sequential protocols using a single 4-mm isocenter targeting the ipsilateral trigeminal nerve at its junction with the pons. The maximum dose was 76 Gy, 87 Gy, or 98 Gy. Patients were followed for a minimum of 6 months and a maximum of 9 years (median 2.4 years). Results: After 6 months, 42% of patients reported an “excellent” response as defined by a complete relief of pain and were no longer taking any medication, and 33% had “good” response as defined by complete relief of pain accompanied by a decrease in the amount of pain medication required. At time of last follow up, 50% of patients had an “excellent” response, and 14% had a “good” response. Forty-five patients (18%) who reported improved symptoms subsequently developed recurrent pain. The mean time to recurrence was 1.8 years (range 0.5 to 6 years). At 12 months following treatment, the percentage of patients reporting an “excellent” or “good” response at dose levels 76 Gy, 87 Gy, and 98 Gy were 70%, 86%, and 86% respectively. Although there was a trend to improved responses at 12 months with the higher radiation dose, this did not reach statistical significance (p⫽0.11). Conclusions: Radiosurgery for trigeminal neuralgia is effective in the majority of cases. The pain relief can occur early and is often durable.
19
FISH Analysis of Genetic Markers of Prognosis for High Grade Astrocyotmas Using Tissue Micro-Arrays from RTOG Clinical Trials
D.J. Brat,1,2 W. Seiferheld,2 A. Perry,3,2 E.H. Hammond,4,2 K.J. Murray,5,2 A. Schulsinger,6,2 M.P. Mehta,7,2 W. Curran8,2 1 Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 2Statistics, Radiation Therapy Oncology Group, Philadelphia, PA, 3Pathology, Washington University School of Medicine, St. Louis, MO, 4Pathology, LDS Hospital, Salt Lake City, UT, 5Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, 6Radiation Oncology, SUNY Health Sciences Center, Brooklyn, NY, 7Human Oncology, University of Wisconsin Medical School, Madison, WI, 8Radiation Oncology, Jefferson Medical College, Philadelphia, PA
Purpose/Objective: Survival varies for patients with high grade astrocytomas. Aside from histologic grade, morphologic features do not reliably predict prognosis. Our goal was to determine if genetic losses from chromosomes 1p, 19q, 9p21, or 10q were associated with long or short survival in anaplastic astrocytoma (AA) and glioblastoma (GBM). We performed fluorescence in situ hybridization (FISH) analysis for these loci on tissue micro-arrays containing 106 high grade astrocytomas from Radiation Therapy Oncology Group (RTOG) clinical trials and correlated the findings with patient survival groups. Materials/Methods: Tissue micro-arrays were constructed using formalin-fixed, paraffin-embedded specimens from 18 AAs and 88 GBMs from RTOG protocols 74-01, 79-03, 79-18, 83-02, 90-06, 93-05, 94-04, 96-02, and 98-06. Cases were selected based on short or long survival. For AA, short and long survivals were ⬍2 yrs and ⬎4 yrs, respectively. For GBM, short and long survivals were ⬍6 mos and ⬎18 mos. Dual-color FISH was performed on 5 micron array sections. For chromosomes 1p and 19q, paired probes were directed at 1p32 and 19q13.4. Paired probes for chromosomes 9p21 and 10q were CEP9/9p21(p16) and CEP10/10q23(PTEN). “Deletion” was defined as ⬎50% nuclei with only one fluorescent signal. Survivals were dichotomized into short- or long-term groups and chromosomal markers were defined as present or deleted. Data was analyzed using Fisher’s exact test of association and logistic regression. AAs and GBMs, 1p and 19q deletions, and 9p21 and 10q deletions were analyzed separately and combined (adjusted p⫽0.025). Results: FISH analysis was possible on 65 to 85 tumors per micro-array depending on the marker. Chromosome 1p deletions were noted in 2 (17%) AAs and 0 GBMs, whereas 19q deletions were noted in 3 (20%) AAs and 7 (10%) GBMs. Combined 1p and 19q loss was detected in 2 (13%) AAs and 0 GBMs. Chromosome 9p21 loss was seen in 5 (63%) AAs and 39 (68%) GBMs. Chromosome 10q loss was detected in 4 (27%) AAs and 48 (71%) GBMs. 19q deletions were more frequent in long term than short term survivors for AAs (43% vs. 0%), GBMs (15% vs. 5%), and AA⫹GBM (20% vs. 4%). 10q deletions were more frequent in short term than long term survivors for AAs (38% vs. 14%), GBMs (75% vs. 66%), and AA⫹GBM (68% vs. 56%). 9p21 deletions were slightly more frequent in short term than long term survivors for AAs (67% vs. 60%), GBMs (72% vs. 64%) and AA⫹GBM (72% vs. 64%). No comparisons were statistically significant. Conclusions: We found that losses of chromosome 1p alone and the combined loss of 1p and 19q were rare events in high grade astrocytomas. This contrasts with oligodendrogliomas, in which combined 1p and 19q loss is frequent (60 –70%) and predictive of prolonged survival. The long-term survival group of high-grade astrocytomas showed a trend towards a higher frequency of 19q loss (p⫽0.041). 9p21 and 10q deletions, generally regarded as late events in the progression to GBM, were slightly more frequent in short term survivors. Long and short-term survival groups of high-grade astrocytomas may have dissimilar frequencies of 19q, 9p21, and 10q deletions. A study of overall patient survival with these genetic markers could address prognostic significance more definitively.
20
Reexamining the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) for Glioblastoma Multiforme (GBM) Patients
E.G. Shaw,1 W. Seiferheld,2 C. Scott,2 C. Coughlin,5 S. Leibel,3 W. Curran,4 M. Mehta6 1 Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, 2Statistics, RTOG, Philadelphia, PA, 3Radiation Oncology, Duke University Medical Center, Durham, NC, 4Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, 5Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, 6Human Oncology, University of Wisconsin Hospital/Medical School, Madison, WI
Purpose/Objective: To determine whether the original RPA classification of malignant glioma patients (pts) could be improved upon by restricting the model to GBM pts, considering additional/different baseline variables, and by adding newer studies to the RTOG malignant glioma database. Materials/Methods: The new RPA considered 42 baseline variables and included 1672 GBM pts, compared to 32 variables and 1288 GBM pts (plus 290 AA) included in the original analysis. In the new analysis, radiation dose assigned rather than radiation dose received was used as the radiation treatment variable. The new analysis included two additional studies (RTOG 90-06 and 94-11), and excluded radiation treatment (RT) alone arms from the original database, such that all patients received BCNU plus RT. In order to compare the models, they were applied to a “test set” of 488 pts on six Phase II RTOG studies (76-11, 79-03, 80-07, 84-09, 95-13, 96-02), and evaluated by calculating explained variation (squared error loss), and determining whether the RPA classes provided statistically significantly distinct survival groups. Results: The original model explained more statistical variation than the new model in the test set of RTOG studies. However, RPA classes V and VI from the original model were not statistically significantly different when applied to the test set of studies, i.e., the variables mental status and radiation dose are no longer required. Therefore, we chose a simplified version of the original RPA model by combining classes V and VI, which results in three classes with statistically significantly distinct survival. This simplified model is easier to apply, since it involves only four variables: age, KPS, extent of resection (gross total or subtotal resection (G/STR) vs biopsy), and neurologic function (working (W⫹) or not working (W⫺)). Applying this simpler version of the original RPA model to the updated glioma database provided the results shown in the table and figure below.
S135
S136
I. J. Radiation Oncology
● Biology ● Physics
Volume 57, Number 2, Supplement, 2003
Conclusions: A simplified version of the original RPA model for only GBM patients combines RPA classes V and VI and results in three distinct prognostic groups defined by age, performance status, extent of resection, and neurologic function. The RTOG will use this simplified RPA classification in future clinical trials.
21
Gamma Knife Radiosurgery for Treatment of Trigeminal Neuralgia
V. Mehta,1,2 R. Meier,1,2 J. Gilrein,2 S. Vermeulen,1,2 R. Young2 1 Radiation Oncology, Swedish Cancer Institute, Seattle, WA, 2Northwest Gamma Knife Center, Swedish Cancer Institute, Seattle, WA
Purpose/Objective: We investigated the clinical outcomes in patients treated with gamma knife radiosurgery for trigeminal neuralgia. Materials/Methods: Two hundred fifty patients with trigeminal neuralgia were treated with gamma knife radiosurgery. One hundred fifteen patients had undergone a prior surgical procedure. None of the patients had multiple sclerosis or tumor associated trigeminal neuralgia. The median patient age was 62. Patients were treated on three sequential protocols using a single 4-mm isocenter targeting the ipsilateral trigeminal nerve at its junction with the pons. The maximum dose was 76 Gy, 87 Gy, or 98 Gy. Patients were followed for a minimum of 6 months and a maximum of 9 years (median 2.4 years). Results: After 6 months, 42% of patients reported an “excellent” response as defined by a complete relief of pain and were no longer taking any medication, and 33% had “good” response as defined by complete relief of pain accompanied by a decrease in the amount of pain medication required. At time of last follow up, 50% of patients had an “excellent” response, and 14% had a “good” response. Forty-five patients (18%) who reported improved symptoms subsequently developed recurrent pain. The mean time to recurrence was 1.8 years (range 0.5 to 6 years). At 12 months following treatment, the percentage of patients reporting an “excellent” or “good” response at dose levels 76 Gy, 87 Gy, and 98 Gy were 70%, 86%, and 86% respectively. Although there was a trend to improved responses at 12 months with the higher radiation dose, this did not reach statistical significance (p⫽0.11). Conclusions: Radiosurgery for trigeminal neuralgia is effective in the majority of cases. The pain relief can occur early and is often durable.