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A preliminary retrospective study with temozolomide and radiotherapy versus radiotherapy alone for the treatment of high-grade gliomas
S378
I. J. Radiation Oncology
● Biology ● Physics
Volume 57, Number 2, Supplement, 2003
Materials/Methods: We examined the clinical records of 51 patients with glial tumors treated with definitive radiation therapy over an approximate 15 year time period. In 21 patients chosen at random, the histopathologic area most representative of each tumor was analyzed immunohistochemically using the PTHrP monoclonal antibody (courtesy, L. Deftos) and a standard ABC immunoperoxidase technique. An antibody dilution of 5 micrograms/ml was used on 5-micron sections to localize PTHrP expression in the cytoplasm of glial tumor cells. Tumors were characterized according to the Daumas-Duport system, with mixed oligoastrocytomas categorized according to the grade of the astrocytic component. Normal cortex, midbrain, and cerebellum were used as negative control tissues, while human umbilical cord was used as a positive control. PTHrP expression was scored using 40⫻ magnification and averaging cellular staining incidence over ten high power fields. Staining intensity was characterized on a semi-quantitative basis, using a 1 (background) to 5 (intense cytoplasmic staining) scale. Median follow-up time approximated 5.5 years overall. Progression-free survival and overall actuarial survival was calculated from the date of commencement of radiation therapy to the date of the last neurologic Karnofsky functional status at the date of last follow-up. Kaplan-Meier statistics were used to analyze the influence of the following potential independent variables with respect to progression-free and overall actuarial survival: age, grade, extent of surgical resection, Karnofsy functional status, radiation dose, and PTHrP expression. Statistical significance was achieved at a p⬍.05 level. Results: Glial tumors overexpressing PTHrP demonstrated a shortened progression-free and overall actuarial survival on Kaplan-Meier analyses (p⬍.05). While this effect was independent of age, sex, radiation dose, Karnofsky functional status, and extent of surgical resection, multivariate analyses indicated that grading of the astrocytic component remained the strongest prognosticator in the clinical setting (p⬍.001). Conclusions: PTHrP may be an important adjunct to standard immunopathologic criteria in the determination of glial tumor response. In spite of the intriguing results, grade remains the most important predictor of progression-free and overall actuarial survival in glial tumors treated definitively with radiation therapy. Further studies on a more expanded patient population, studied prospectively, will be necessary before translation into the clinic. Basic studies are warranted investigating role(s) for PTHrP in modulating signal transduction, before and after irradiation.
2059
A Preliminary Retrospective Study with Temozolomide and Radiotherapy Versus Radiotherapy Alone for the Treatment of High-Grade Gliomas
P. Corsa 1
General Hospital, San Giovanni Rotondo, Italy, 2UO Radioterapia IRCCS, Universit Degli Studi Di Bari, Rotondo FG, Italy Purpose/Objective: Temozolomide (TMZ) is a new, orally administered, second-generation imidazotetrazine prodrug with essentially 100% oral bioavailability that has demonstrated meaningful efficacy and acceptable safety profile in the treatment of patients with anaplastic astrocytoma and glioblastoma multiforme. Because of its unique properties and broad spectrum of anticancer activity, preliminary studies are being conducted to evaluate the efficacy of TMZ in combination with radiation therapy in the treatment of patients (pts) with high-grade gliomas. This study was performed at the Department of Radiotherapy of Casa Sollievo della Sofferenza Hospital of San Giovanni Rotondo and at Department of Radiotherapy of University of Bari, in Italy. We retrospectively reviewed the clinical reports of 130 consecutive pts affected by high-grade gliomas: 65 treated with radiotherapy and TMZ (concomitant and/or adjuvant) from January 1997 to November 2001; 65 (historical group) treated with radiotherapy alone from April 1994 to December 1996. We analysed safety, tolerability, and efficacy of combined therapy compared with radiotherapy alone.
Materials/Methods: Between April 1994 and November 2001, 130 pts (74 males and 56 females), affected by high grade gliomas (34 anaplastic astrocytoma, 3 anaplastic oligodendroglioma and 93 glioblastoma multiforme), were treated with external beam radiotherapy plus TMZ (65 pts) and with external beam radiation therapy alone (65 pts). The pts age ranged between 26 and 78 years (mean 57 y.o.). The Karnofsky Index in most of the pts ranged from 70% to 80%. 53 pts. underwent to complete surgical resection and 55 pts to subtotal resection. In 22 pts. only stereotactic biopsy was performed. In group 1, 34 pts were treated with radiotherapy and orally concomitant TMZ (75 mg/m2/d ⫻ 7 d/wk for 6 weeks) followed by adjuvant TMZ (200 mg/m2/d x 5 days, every 28 days) and 31 pts with only adjuvant TMZ (200 mg/m2/d ⫻ 5 days, every 28 days). In group 2 65 pts were treated with external beam radiotherapy alone. In all pts the radiation therapy medium total dose was 60 Gy with conventional fractionation. We employed 6 MV photons Linac in 35 pts, 8 MV photons Linac in 22 and 60Co in 73. The primary end points analysed were safety and tolerability, and the secondary end point was overall survival. Results Results: Concomitant radiation plus TMZ therapy and/or adjuvant TMZ was safe and well tolerated. The haematological side effects were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 neutropenia, thrombocytopenia, or both were observed in 6,2% of patients. During adjuvant TMZ, 3% of pts. were associated with grade 3 neutropenia and thrombocytopenia. At this time 21 pts (16.2%) are alive and 109 pts (83.8%) are died. On the basis of Kaplan-Meier estimates, the median survival was 15 months (without TMZ 14 months and with TMZ 16 months): T site, age, histology and administration of TMZ were statistically significant in the univariate analysis for 2- years overall survival using Kaplan Meier method and compared with log-rank test: age ⬍ 65 y.o. 24.5% vs ⬎ 65 y.o 6.4% (p ⫽ 0.004); concomitant and adjuvant TMZ administration 33.4%, vs radiotherapy alone 8% (p ⫽ 0.0009); anaplastic astrocytoma 42.3% vs glioblastoma multiforme 11.4% (p ⫽ 0.0001); frontal and occipital sites 24.5% vs temporal and parietal sites 14,6% (p ⫽ 0.05). In a multivariate analysis using stratified Cox regression, the variables that were significantly associated with better overall survival were age (p ⫽ 0.008), histology (p ⫽ 0.003) and administration of TMZ (p ⫽ 0.001). Conclusions: Continuous daily TMZ and concomitant radiation or external radiotherapy followed by adjuvant TMZ are safe and may prolong survival in pts with high grade gliomas. Further investigation is warranted.
I. J. Radiation Oncology
● Biology ● Physics
Volume 57, Number 2, Supplement, 2003
Materials/Methods: We examined the clinical records of 51 patients with glial tumors treated with definitive radiation therapy over an approximate 15 year time period. In 21 patients chosen at random, the histopathologic area most representative of each tumor was analyzed immunohistochemically using the PTHrP monoclonal antibody (courtesy, L. Deftos) and a standard ABC immunoperoxidase technique. An antibody dilution of 5 micrograms/ml was used on 5-micron sections to localize PTHrP expression in the cytoplasm of glial tumor cells. Tumors were characterized according to the Daumas-Duport system, with mixed oligoastrocytomas categorized according to the grade of the astrocytic component. Normal cortex, midbrain, and cerebellum were used as negative control tissues, while human umbilical cord was used as a positive control. PTHrP expression was scored using 40⫻ magnification and averaging cellular staining incidence over ten high power fields. Staining intensity was characterized on a semi-quantitative basis, using a 1 (background) to 5 (intense cytoplasmic staining) scale. Median follow-up time approximated 5.5 years overall. Progression-free survival and overall actuarial survival was calculated from the date of commencement of radiation therapy to the date of the last neurologic Karnofsky functional status at the date of last follow-up. Kaplan-Meier statistics were used to analyze the influence of the following potential independent variables with respect to progression-free and overall actuarial survival: age, grade, extent of surgical resection, Karnofsy functional status, radiation dose, and PTHrP expression. Statistical significance was achieved at a p⬍.05 level. Results: Glial tumors overexpressing PTHrP demonstrated a shortened progression-free and overall actuarial survival on Kaplan-Meier analyses (p⬍.05). While this effect was independent of age, sex, radiation dose, Karnofsky functional status, and extent of surgical resection, multivariate analyses indicated that grading of the astrocytic component remained the strongest prognosticator in the clinical setting (p⬍.001). Conclusions: PTHrP may be an important adjunct to standard immunopathologic criteria in the determination of glial tumor response. In spite of the intriguing results, grade remains the most important predictor of progression-free and overall actuarial survival in glial tumors treated definitively with radiation therapy. Further studies on a more expanded patient population, studied prospectively, will be necessary before translation into the clinic. Basic studies are warranted investigating role(s) for PTHrP in modulating signal transduction, before and after irradiation.
2059
A Preliminary Retrospective Study with Temozolomide and Radiotherapy Versus Radiotherapy Alone for the Treatment of High-Grade Gliomas
P. Corsa 1
General Hospital, San Giovanni Rotondo, Italy, 2UO Radioterapia IRCCS, Universit Degli Studi Di Bari, Rotondo FG, Italy Purpose/Objective: Temozolomide (TMZ) is a new, orally administered, second-generation imidazotetrazine prodrug with essentially 100% oral bioavailability that has demonstrated meaningful efficacy and acceptable safety profile in the treatment of patients with anaplastic astrocytoma and glioblastoma multiforme. Because of its unique properties and broad spectrum of anticancer activity, preliminary studies are being conducted to evaluate the efficacy of TMZ in combination with radiation therapy in the treatment of patients (pts) with high-grade gliomas. This study was performed at the Department of Radiotherapy of Casa Sollievo della Sofferenza Hospital of San Giovanni Rotondo and at Department of Radiotherapy of University of Bari, in Italy. We retrospectively reviewed the clinical reports of 130 consecutive pts affected by high-grade gliomas: 65 treated with radiotherapy and TMZ (concomitant and/or adjuvant) from January 1997 to November 2001; 65 (historical group) treated with radiotherapy alone from April 1994 to December 1996. We analysed safety, tolerability, and efficacy of combined therapy compared with radiotherapy alone.
Materials/Methods: Between April 1994 and November 2001, 130 pts (74 males and 56 females), affected by high grade gliomas (34 anaplastic astrocytoma, 3 anaplastic oligodendroglioma and 93 glioblastoma multiforme), were treated with external beam radiotherapy plus TMZ (65 pts) and with external beam radiation therapy alone (65 pts). The pts age ranged between 26 and 78 years (mean 57 y.o.). The Karnofsky Index in most of the pts ranged from 70% to 80%. 53 pts. underwent to complete surgical resection and 55 pts to subtotal resection. In 22 pts. only stereotactic biopsy was performed. In group 1, 34 pts were treated with radiotherapy and orally concomitant TMZ (75 mg/m2/d ⫻ 7 d/wk for 6 weeks) followed by adjuvant TMZ (200 mg/m2/d x 5 days, every 28 days) and 31 pts with only adjuvant TMZ (200 mg/m2/d ⫻ 5 days, every 28 days). In group 2 65 pts were treated with external beam radiotherapy alone. In all pts the radiation therapy medium total dose was 60 Gy with conventional fractionation. We employed 6 MV photons Linac in 35 pts, 8 MV photons Linac in 22 and 60Co in 73. The primary end points analysed were safety and tolerability, and the secondary end point was overall survival. Results Results: Concomitant radiation plus TMZ therapy and/or adjuvant TMZ was safe and well tolerated. The haematological side effects were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 neutropenia, thrombocytopenia, or both were observed in 6,2% of patients. During adjuvant TMZ, 3% of pts. were associated with grade 3 neutropenia and thrombocytopenia. At this time 21 pts (16.2%) are alive and 109 pts (83.8%) are died. On the basis of Kaplan-Meier estimates, the median survival was 15 months (without TMZ 14 months and with TMZ 16 months): T site, age, histology and administration of TMZ were statistically significant in the univariate analysis for 2- years overall survival using Kaplan Meier method and compared with log-rank test: age ⬍ 65 y.o. 24.5% vs ⬎ 65 y.o 6.4% (p ⫽ 0.004); concomitant and adjuvant TMZ administration 33.4%, vs radiotherapy alone 8% (p ⫽ 0.0009); anaplastic astrocytoma 42.3% vs glioblastoma multiforme 11.4% (p ⫽ 0.0001); frontal and occipital sites 24.5% vs temporal and parietal sites 14,6% (p ⫽ 0.05). In a multivariate analysis using stratified Cox regression, the variables that were significantly associated with better overall survival were age (p ⫽ 0.008), histology (p ⫽ 0.003) and administration of TMZ (p ⫽ 0.001). Conclusions: Continuous daily TMZ and concomitant radiation or external radiotherapy followed by adjuvant TMZ are safe and may prolong survival in pts with high grade gliomas. Further investigation is warranted.