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197 oral Temozolamide (TMZ) combined with radiotherapy (RT) in high-grade gliomas: preliminary results
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Friday, 2 February 2001
Proffered papers CNS TUMOURS 196
oral
A phase II trial of primary chemotherapy with Temozolomide in patients with low-grade cerebral gliomas. L. Viviers 1, P. Murphy 1, J. Britton 2, C. Abson 1, F. Hines 1, M. Brada 1 1The Institute of Cancer Research and The Royal Marsden Hospital, Neuro-oncology, London, UK 2Atkinson Morley's Hospital, Neuro-radiology, London, UK Aims: To assess the efficacy of Temozolomide in a Phase II study in patients with low-grade glioma who had no previous antitumour therapy other than surgery and had measurable disease on neuro-imaging. Methods: Patients received Temozolomide (200 mg/m=/day for 5 consecutive days) on a 28-day cycle for a maximum of 12 cycles or until tumour progression. Response was measured by 3-monthly MRI, monthly clinical evaluation and health-related quality of life assessment using a validated instrument. MR images were evaluated by 3 independent observers. The tumour size was calculated as the product of the largest perpendicular dimensions of the high signal intensity region on axial FLAIR images. In addition, in 12 patients the metabolic response to Temozolomide was measured using 1H-MR Spectroscopy. Patients: Between March 1998 and January 2000, 18 patients with WHO grade II astrocytoma and 12 with oligodendroglioma were enrolled. 15 patients had biopsy alone and 12 incomplete resection. Of the 30 patients, 27 were evaluable for response (12 men, 15 women; median age of 42 years). Three patients were excluded, one due to radio[ogical malignant transformation, another due to lactose intolerance and one with gliomatosis cerebri which was not measurable. Median follow up is 16 months. Results: Fifteen patients completed 12 months of treatment and 9 patients 6 months of treatment. 17/18 symptomatic patients experienced clinical benefit with improvement in symptoms and HQL scores. All patients had a slow initial reduction in tumour size. The mean reduction was 29% (range 10-48%) at 6 months and 32% (range 32 - 52%) at 12 months. In patients assessed by spectroscopy, the decrease in tumour size was clearly matched by a decrease in the choline - water ratio. Two patients showed radiological progression at 6 and at 9 months respectively after a short initial response. Of 24 patients who received a minimum of 6 cycles of chemotherapy 3/24 had PR, 18/24 MR and 3/24 SD. One patient died of unrelated causes (presumed IHD). Grade 3/4 haematolegical toxicity occurred in one patient. Conclusions: Preliminary results of this ongoing trial suggest that Temozolomide has single agent activity in the treatment of patients with lowgrade cerebral glioma. 197
oral
Temozolamide (TMZ) combined with radiotherapy (RT) in high-grade gliomas : preliminary results. A. Tagliagambe 3, L. Fatigante 1, A.M. Nocita 1, R. Cantini2, L. Lutzenberge~, M. Bergamini4, S. Luxardo 4, R. Massetani 5, L. Barbieri 3, L. Cionini 1 1Radiotherapy Department, Pisa University, Italy 2Neurosurgery Division, Pisa University, Italy 3Radiation Unit, Oncological Department, Carrara, Italy 4physics Service, Civic Hospital, Carrara, Italy 5Neurological Unit, Oncolgical Department, Carrara, Italy Temozolamide (TMZ) has shown encouraging clinical activity for progressive or recurrent brain turnouts. We refer our data regarding post-operative high-grade glioma treatment with the aim to evaluate toxicity and efficacy on tumor control, of TMZ combined with radiotherapy in patients with high grade gliomas treated after biopsy or removal of the main mass. Methods: Since May 1998, 37 patients (pts) with brain tumors have been treated with RT and TMZ at the Radiation Units of Pisa and Carrara. 32 pts (24 M and 8 F) were evaluabie; histology : 25 glioblastoma multiforme, 6 anaplastic astrocitoma, 1 anaplastic oligo-dendroglioma ; surgery :5 stereotactJc biopsy, 8 partial resection, 9 subtotal excision, 10 radical exci-
sion; age : median 58 years ( range 25-84); p.s. : median 1 (ECOG) ; follow-up: median 16 months. TMZ was given both concomitant to RT (75 mg/mq p.os daily 5 days/week) and sequential (350 mg/mq day 1-5 every 28). 23 pts were given TMZ + RT concomitant, 9 also received TMZ sequential. RT was delivered with Linac (5-6 Mev), multiple shaped fields (median 3), conventional fractionation (2 Gy/fr.). Total dose (TD) given to the CTV was : 70 Gy (12 pts.), 60-66 Gy (16 pts), 44-52 Gy (3 pts).The mean number of sequential TMZ cycles was 5.5. Toxicity In RT and TMZ concomitant : nausea in 2 pts (1 pts G1,1 pts G2); sequential TMZ treatment: thrombocytopenia in 4 pts. (3 pts G1, 1 pts G2), and neutropenia in 2 pts (1 pts G1, 1 pts G2). Results: Clinical response evaluated by CT/MR at 3 months after completion of RT-TMZ treatment : 13 CR, 6 PR, 4 SD ; in the sequential TMZ group : 2 CR, 1 PR, 5 SD and 1 PD. Data on quality of life and progression free survival are under evaluation. Conclusions: Concomitant TMZ + RT in high grade gliomas after surgery, is well tolerated with mild gastrointestinal toxicity and results in a satisfactory tumor control. The monthly sequential use of TMZ gives acceptable myelotoxicity. 198
oral
Acute toxicity of an adjuvant radiochemotherapy (RCT) with temozolomide (TMZ) in patients with newly diagnosed primary high grade brain tumors D. Trog 1, A. Rahn 1, K. Franz2, S. Mose 1, V. Seifert2, H. Boettcher 1 1johann-Wolfgang-Goethe-University, Radiooncology, Frankfurt, Germany 2Johann-Wolfgang-Goethe-University, Neurosurgery, Frankfurt, Germany Purpose: The prognosis of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) is poor, due to the lack of an effective therapy. Temozolomide is a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumors. Therefore we evaluated the feasibility and acute toxicity of a daily administration of Temozolomide (TMZ) during a radiotherapy (RT) of patients (pts.) with primary grade Ill or IV brain tumors. Furthermore we examined the efficacy of a combined RCT with regard to the Iocoregional tumor control and the overall survival. Purpose: The prognosis of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) is poor, due to the lack of an effective therapy. Therefore we evaluated the feasibility and acute toxicity of a daily administration of Temozolomide (TMZ) during a radiotherapy (RT) of patients (pts.) with primary grade III or IV brain tumors. Furthermore we examined the efficacy of a combined RCT with regard to the Iocoregional tumor control and the overall survival. Patients/Methods: 20 pts. with GBM grade IV (n=14) and AA (n=6) were treated by RT and concomitant oral therapy with TMZ in a prospective pilot trial. According to the postoperative MR112/20 pts. showed no evidence of tumor, 6/20 pat. had only a partial tumor resection and 2/20 patients had only a biopsy. In all pts the primary tumor site was irradiated with a total dose of 60 Gy and a daily fraction of 2 Gy. Simultaneously they received 75 mg/m2/d TMZ daily. In case of relapse the pts. are supposed to be treated with 200 mg/d TMZ for 5 d in 28/d cycles. Results: The toxicity analysis revealed one grad IV myelosuppression, without major complication, four grade I headache, six grade I-II fatigue and six grade I-II nausea. 6 weeks after the end of combined therapy 18/20 pts were reevaluated and from this 12 pts showed no tumor relapse in the MRI-control. Patients with postoperative tumor remnants showed in 4 cases partial responses and in 2 cases stable diseases. Further controls indicated after 3 months in 7/10 pts., after 6 months in 4/6 pts and after 9 months in 3/4 pts no tumor relapse. Conclusion: The major toxicity were grade I-II nausea and hematological side effects, No cumulative side effects were observed, but the data emphasize the importance of periodically blood control. After a median follow up of 3 months this therapy appears to be effective, because no patient showed a tumor progression or a tumor recurrence (after MRI control ) so far. Furthermore in 4 cases with postoperative tumor remnants the control showed a partial response.
Friday, 2 February 2001
Proffered papers CNS TUMOURS 196
oral
A phase II trial of primary chemotherapy with Temozolomide in patients with low-grade cerebral gliomas. L. Viviers 1, P. Murphy 1, J. Britton 2, C. Abson 1, F. Hines 1, M. Brada 1 1The Institute of Cancer Research and The Royal Marsden Hospital, Neuro-oncology, London, UK 2Atkinson Morley's Hospital, Neuro-radiology, London, UK Aims: To assess the efficacy of Temozolomide in a Phase II study in patients with low-grade glioma who had no previous antitumour therapy other than surgery and had measurable disease on neuro-imaging. Methods: Patients received Temozolomide (200 mg/m=/day for 5 consecutive days) on a 28-day cycle for a maximum of 12 cycles or until tumour progression. Response was measured by 3-monthly MRI, monthly clinical evaluation and health-related quality of life assessment using a validated instrument. MR images were evaluated by 3 independent observers. The tumour size was calculated as the product of the largest perpendicular dimensions of the high signal intensity region on axial FLAIR images. In addition, in 12 patients the metabolic response to Temozolomide was measured using 1H-MR Spectroscopy. Patients: Between March 1998 and January 2000, 18 patients with WHO grade II astrocytoma and 12 with oligodendroglioma were enrolled. 15 patients had biopsy alone and 12 incomplete resection. Of the 30 patients, 27 were evaluable for response (12 men, 15 women; median age of 42 years). Three patients were excluded, one due to radio[ogical malignant transformation, another due to lactose intolerance and one with gliomatosis cerebri which was not measurable. Median follow up is 16 months. Results: Fifteen patients completed 12 months of treatment and 9 patients 6 months of treatment. 17/18 symptomatic patients experienced clinical benefit with improvement in symptoms and HQL scores. All patients had a slow initial reduction in tumour size. The mean reduction was 29% (range 10-48%) at 6 months and 32% (range 32 - 52%) at 12 months. In patients assessed by spectroscopy, the decrease in tumour size was clearly matched by a decrease in the choline - water ratio. Two patients showed radiological progression at 6 and at 9 months respectively after a short initial response. Of 24 patients who received a minimum of 6 cycles of chemotherapy 3/24 had PR, 18/24 MR and 3/24 SD. One patient died of unrelated causes (presumed IHD). Grade 3/4 haematolegical toxicity occurred in one patient. Conclusions: Preliminary results of this ongoing trial suggest that Temozolomide has single agent activity in the treatment of patients with lowgrade cerebral glioma. 197
oral
Temozolamide (TMZ) combined with radiotherapy (RT) in high-grade gliomas : preliminary results. A. Tagliagambe 3, L. Fatigante 1, A.M. Nocita 1, R. Cantini2, L. Lutzenberge~, M. Bergamini4, S. Luxardo 4, R. Massetani 5, L. Barbieri 3, L. Cionini 1 1Radiotherapy Department, Pisa University, Italy 2Neurosurgery Division, Pisa University, Italy 3Radiation Unit, Oncological Department, Carrara, Italy 4physics Service, Civic Hospital, Carrara, Italy 5Neurological Unit, Oncolgical Department, Carrara, Italy Temozolamide (TMZ) has shown encouraging clinical activity for progressive or recurrent brain turnouts. We refer our data regarding post-operative high-grade glioma treatment with the aim to evaluate toxicity and efficacy on tumor control, of TMZ combined with radiotherapy in patients with high grade gliomas treated after biopsy or removal of the main mass. Methods: Since May 1998, 37 patients (pts) with brain tumors have been treated with RT and TMZ at the Radiation Units of Pisa and Carrara. 32 pts (24 M and 8 F) were evaluabie; histology : 25 glioblastoma multiforme, 6 anaplastic astrocitoma, 1 anaplastic oligo-dendroglioma ; surgery :5 stereotactJc biopsy, 8 partial resection, 9 subtotal excision, 10 radical exci-
sion; age : median 58 years ( range 25-84); p.s. : median 1 (ECOG) ; follow-up: median 16 months. TMZ was given both concomitant to RT (75 mg/mq p.os daily 5 days/week) and sequential (350 mg/mq day 1-5 every 28). 23 pts were given TMZ + RT concomitant, 9 also received TMZ sequential. RT was delivered with Linac (5-6 Mev), multiple shaped fields (median 3), conventional fractionation (2 Gy/fr.). Total dose (TD) given to the CTV was : 70 Gy (12 pts.), 60-66 Gy (16 pts), 44-52 Gy (3 pts).The mean number of sequential TMZ cycles was 5.5. Toxicity In RT and TMZ concomitant : nausea in 2 pts (1 pts G1,1 pts G2); sequential TMZ treatment: thrombocytopenia in 4 pts. (3 pts G1, 1 pts G2), and neutropenia in 2 pts (1 pts G1, 1 pts G2). Results: Clinical response evaluated by CT/MR at 3 months after completion of RT-TMZ treatment : 13 CR, 6 PR, 4 SD ; in the sequential TMZ group : 2 CR, 1 PR, 5 SD and 1 PD. Data on quality of life and progression free survival are under evaluation. Conclusions: Concomitant TMZ + RT in high grade gliomas after surgery, is well tolerated with mild gastrointestinal toxicity and results in a satisfactory tumor control. The monthly sequential use of TMZ gives acceptable myelotoxicity. 198
oral
Acute toxicity of an adjuvant radiochemotherapy (RCT) with temozolomide (TMZ) in patients with newly diagnosed primary high grade brain tumors D. Trog 1, A. Rahn 1, K. Franz2, S. Mose 1, V. Seifert2, H. Boettcher 1 1johann-Wolfgang-Goethe-University, Radiooncology, Frankfurt, Germany 2Johann-Wolfgang-Goethe-University, Neurosurgery, Frankfurt, Germany Purpose: The prognosis of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) is poor, due to the lack of an effective therapy. Temozolomide is a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumors. Therefore we evaluated the feasibility and acute toxicity of a daily administration of Temozolomide (TMZ) during a radiotherapy (RT) of patients (pts.) with primary grade Ill or IV brain tumors. Furthermore we examined the efficacy of a combined RCT with regard to the Iocoregional tumor control and the overall survival. Purpose: The prognosis of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) is poor, due to the lack of an effective therapy. Therefore we evaluated the feasibility and acute toxicity of a daily administration of Temozolomide (TMZ) during a radiotherapy (RT) of patients (pts.) with primary grade III or IV brain tumors. Furthermore we examined the efficacy of a combined RCT with regard to the Iocoregional tumor control and the overall survival. Patients/Methods: 20 pts. with GBM grade IV (n=14) and AA (n=6) were treated by RT and concomitant oral therapy with TMZ in a prospective pilot trial. According to the postoperative MR112/20 pts. showed no evidence of tumor, 6/20 pat. had only a partial tumor resection and 2/20 patients had only a biopsy. In all pts the primary tumor site was irradiated with a total dose of 60 Gy and a daily fraction of 2 Gy. Simultaneously they received 75 mg/m2/d TMZ daily. In case of relapse the pts. are supposed to be treated with 200 mg/d TMZ for 5 d in 28/d cycles. Results: The toxicity analysis revealed one grad IV myelosuppression, without major complication, four grade I headache, six grade I-II fatigue and six grade I-II nausea. 6 weeks after the end of combined therapy 18/20 pts were reevaluated and from this 12 pts showed no tumor relapse in the MRI-control. Patients with postoperative tumor remnants showed in 4 cases partial responses and in 2 cases stable diseases. Further controls indicated after 3 months in 7/10 pts., after 6 months in 4/6 pts and after 9 months in 3/4 pts no tumor relapse. Conclusion: The major toxicity were grade I-II nausea and hematological side effects, No cumulative side effects were observed, but the data emphasize the importance of periodically blood control. After a median follow up of 3 months this therapy appears to be effective, because no patient showed a tumor progression or a tumor recurrence (after MRI control ) so far. Furthermore in 4 cases with postoperative tumor remnants the control showed a partial response.