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SP-0531: Chordoma: current concepts management and future directions
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ESTRO 33, 2014 There is a higher wound complication rate after preoperative RT with a diminished quality of life in the first half year. However, with prolonged follow-up, the lower doses and smaller volumes translate into substantially better functioning extremities. There is one caveat: in case of disagreement between the results of the diagnostic (core needle) biopsy and the MRI findings, either a repeat biopsy should be performed or definitive surgery should be considered first. Ongoing and planned studies Several sarcoma groups investigate the feasibility of combining angiogenesis inhibitors with preoperative RT. In myxoid liposarcomas lowering the conventional dose of 50Gy is investigated. It may well be that the standard fraction size of 2 Gy is suboptimal for some if not all subtypes. In the past, hyperfractionation trials were negative in almost all endpoints studied, but hypofractionation has not been studied thoroughly yet. Irradiating ESTS patients prior to surgery offers the unique opportunity to perform translational research on several domains like vasculature, tumor perfusion and diffusion, radiation sensitivity, molecular biomarkers etc. Hereby we will further unravel the biology of specific sarcoma subtypes hopefully resulting in personalized patient care. In summary Sequencing radiotherapy in ESTS patients should not be the same for all: some are best managed by surgery only and for those in need of combined management a personalized decision balancing wound complications to late functional morbidity should be made. SP-0531 Chordoma: current concepts management and future directions J. Debus1 University of Heidelberg, Radiation Oncology, Heidelberg, Germany Chordomas are rare bone tumors, which develop from remnants of the notochord. The most common sites are the sacrum, the skull base and the spine. Due to the low incidence of metastasis, local control is the most important factor for survival. Local treatment with surgery and radiation therapy is still the standard in non-metastatic chordoma and resulted in higher control rates and better overall survival in most of the data. Radiotherapy always seems to be indicated, even after an apparently complete resection due to the potential of scattered cell clusters at some distance to the main tumor. Therapy with protons or carbon ions seems to ensue in higher local control rates compared to photon therapy. The advantage arises from the possibility of dose escalation for this relatively radioresistent tumor. In addition, there is some evidence that the treatment with carbon ions has an increased biological effect. So far, there are no prospective randomized studies showing the superiority of proton therapy compared with a modern photon IMRT therapy. Furthermore, the role of heavy ions is still unclear at the present time. In general it has been shown by many investigators that chordoma are tumors, which can be controlled by radiotherapy. There is a steep dose response relationship, which may allow a high control in patients, if high doses of radiation can be delivered. In some other tumor entities, radiotherapy alone has been shown as an equivalent method compared to surgery with the same tumor control. This raises the question whether radiotherapy after biopsy only can lead to the same local control in chordoma patients as compared to surgery. Data from Boston showed no significant difference after radiation treatment in local control of spinal chordomas between R0 resection and biopsy, R2, or R1 resection. Japanese data of inoperable sacral chordomas showed high local control after irradiation with carbon ions only. Since there is some evidence that a biopsy compared to a R0 resection followed by radiation therapy has no significant differences in local control, randomized trials comparing surgery only or in combination with radiation treatment versus radiation only are required. A milestone in chordoma research was the identification of gene duplication of the transcriptional regulator brachyury in patients with familial and sporadic chordoma disease. The expression of brachyury cannot only be used as a diagnostic marker, but may also be the key to a new treatment. Brachyury is a very important factor during the development of the notochord in embryos and is later unexpressed in normal tissue. Brachyury expression is high exclusively in chordoma cells. Brachyury seems to be the key of chordoma development, and thus can be used as a therapy target. There are several points that make the research in the field of chordoma a challenge. Chordoma is a rare disease, which leads to the most apparent clinical results from retrospective data of small groups of patients. Prospective studies, which have a higher degree of evidence, are difficult to perform due to the rarity of the disease. A second point is the slow growth of chordoma cells. For a long time, there was no cell line for research and currently most cell lines are derived from sacral chordoma, which show, in most of the cases, a higher proliferation rate compared to skull base chordoma cells.
SYMPOSIUM: INDIVIDUALISATION OF TREATMENT FOR PATIENTS WITH HIGH GRADE GLIOMA SP-0532 Molecular biomarkers in glioma: Prognostic or predictive? W. Wick1 1 University Hospital Heidelberg, Deaprtment of Neurooncology, Heidelberg, Germany Promoter methylation of the O6-methyl-guaninemethyl transferase gene is considered relevant for treatment with alkylating chemotherapies for almost 15 years. Ten years ago the EORTC26981/22981 NCIC CE.3 trial demonstrated a predictive role for MGMT promoter methylation in patients with gliobastoma treated with temozolomide. Two phase trials in elderly patients confirmed that predictive role for the MGMT status resulting in a modification of clinical practice. In anaplastic gliomas, both the codeletion of 1p/19q as well as the MGMT promoter methylation are predictive for combined radiochemotherapy or alkylating (radio-) chemotherapy, respectively. The role of MGMT isdependent on mutation status of isocitratede hydrogenase, as mutated IDH confers a glioma CpG island methylator phenotype, both being prognostic and making also MGMT a prognostic biomarker. In the wild-type IDHsetting, MGMT is predictive. Other relevant prognostic parameters are loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene. More recently, also expression of n-myc downstream regulated gene 1 (NDRG1) has been associated with resistance to alkylating chemotherapy and CD95 ligand expression with response to anti-CD9 5ligand-directed therapy. SP-0533 Maximising benefit and minimising risk in the treatment of elderly patients with glioblastoma N. Laperriere1 1 Princess Margaret Cancer Centre, Radiation Oncology, Toronto, Canada The standard of care for patients with glioblastoma age 70 or less with a WHO performance status of 2 or better has been established as 6 weeks of radiotherapy with daily concurrent temozolomide and 6 months of adjuvant temozolomide. Subsequent analysis of this trial revealed a declining benefit of the addition of temozolomide to radiotherapy with increasing age, such that the benefit for patients older than 60 did not reach statistical significance. Population based data show a diminishing benefit from any treatment with older age, such that one must exercise caution in administering potentially toxic therapy to older patients with glioblastoma. A French randomized trial of post-operative radiotherapy versus supportive care to patients with glioblastoma age 70 or older demonstrated an improved median survival of 29 versus 17 weeks in 85 patients with a KPS of 70 or better. A Canadian randomized trial of 40 Gy in 15 fractions versus 60 Gy in 30 fractions in 100 patients age 60 or older revealed a median survival of 5.6 months for the 40 Gy arm versus 5.1 months for the 60Gy arm, no statistical difference. The Nordic randomized trial in patients age 60 and older incorporated 2 radiotherapy arms of 34 Gy in 10 fractions versus 60 Gy in 30 fractions, and there was no statistically significant difference in survival found between these 2 arms, but in patients age older than 70, there was a statistically significant reduction in survival for the 60 Gy arm versus the 34 Gy arm, suggesting possible toxicity of the higher dose arm as the possible reason for this difference. The NOA-08 German randomized trial of radiotherapy (54-60 Gy in 30) versus temozolomide (days 1-7, days 1521) found no statistical difference in survival, but did find that MGMT promoter methylated patients had better survival with temozolomide as opposed to radiotherapy, and vice versa for patients with unmethylated tumours, suggesting a possible strategy of temozolomide only for methylated patients and radiotherapy only for unmethylated patients. The NCIC CTG-EORTC randomized trial of 40 Gy in 15 fractions with and without concurrent and adjuvant temozolomide has recently completed accrual of 562 patients, and will provide data on the possible benefit of short course radiotherapy with temozolomide as an option for elderly patients with glioblastoma.
SP-0534 Do patients with glioblastoma benefit from IMRT?
ESTRO 33, 2014 There is a higher wound complication rate after preoperative RT with a diminished quality of life in the first half year. However, with prolonged follow-up, the lower doses and smaller volumes translate into substantially better functioning extremities. There is one caveat: in case of disagreement between the results of the diagnostic (core needle) biopsy and the MRI findings, either a repeat biopsy should be performed or definitive surgery should be considered first. Ongoing and planned studies Several sarcoma groups investigate the feasibility of combining angiogenesis inhibitors with preoperative RT. In myxoid liposarcomas lowering the conventional dose of 50Gy is investigated. It may well be that the standard fraction size of 2 Gy is suboptimal for some if not all subtypes. In the past, hyperfractionation trials were negative in almost all endpoints studied, but hypofractionation has not been studied thoroughly yet. Irradiating ESTS patients prior to surgery offers the unique opportunity to perform translational research on several domains like vasculature, tumor perfusion and diffusion, radiation sensitivity, molecular biomarkers etc. Hereby we will further unravel the biology of specific sarcoma subtypes hopefully resulting in personalized patient care. In summary Sequencing radiotherapy in ESTS patients should not be the same for all: some are best managed by surgery only and for those in need of combined management a personalized decision balancing wound complications to late functional morbidity should be made. SP-0531 Chordoma: current concepts management and future directions J. Debus1 University of Heidelberg, Radiation Oncology, Heidelberg, Germany Chordomas are rare bone tumors, which develop from remnants of the notochord. The most common sites are the sacrum, the skull base and the spine. Due to the low incidence of metastasis, local control is the most important factor for survival. Local treatment with surgery and radiation therapy is still the standard in non-metastatic chordoma and resulted in higher control rates and better overall survival in most of the data. Radiotherapy always seems to be indicated, even after an apparently complete resection due to the potential of scattered cell clusters at some distance to the main tumor. Therapy with protons or carbon ions seems to ensue in higher local control rates compared to photon therapy. The advantage arises from the possibility of dose escalation for this relatively radioresistent tumor. In addition, there is some evidence that the treatment with carbon ions has an increased biological effect. So far, there are no prospective randomized studies showing the superiority of proton therapy compared with a modern photon IMRT therapy. Furthermore, the role of heavy ions is still unclear at the present time. In general it has been shown by many investigators that chordoma are tumors, which can be controlled by radiotherapy. There is a steep dose response relationship, which may allow a high control in patients, if high doses of radiation can be delivered. In some other tumor entities, radiotherapy alone has been shown as an equivalent method compared to surgery with the same tumor control. This raises the question whether radiotherapy after biopsy only can lead to the same local control in chordoma patients as compared to surgery. Data from Boston showed no significant difference after radiation treatment in local control of spinal chordomas between R0 resection and biopsy, R2, or R1 resection. Japanese data of inoperable sacral chordomas showed high local control after irradiation with carbon ions only. Since there is some evidence that a biopsy compared to a R0 resection followed by radiation therapy has no significant differences in local control, randomized trials comparing surgery only or in combination with radiation treatment versus radiation only are required. A milestone in chordoma research was the identification of gene duplication of the transcriptional regulator brachyury in patients with familial and sporadic chordoma disease. The expression of brachyury cannot only be used as a diagnostic marker, but may also be the key to a new treatment. Brachyury is a very important factor during the development of the notochord in embryos and is later unexpressed in normal tissue. Brachyury expression is high exclusively in chordoma cells. Brachyury seems to be the key of chordoma development, and thus can be used as a therapy target. There are several points that make the research in the field of chordoma a challenge. Chordoma is a rare disease, which leads to the most apparent clinical results from retrospective data of small groups of patients. Prospective studies, which have a higher degree of evidence, are difficult to perform due to the rarity of the disease. A second point is the slow growth of chordoma cells. For a long time, there was no cell line for research and currently most cell lines are derived from sacral chordoma, which show, in most of the cases, a higher proliferation rate compared to skull base chordoma cells.
SYMPOSIUM: INDIVIDUALISATION OF TREATMENT FOR PATIENTS WITH HIGH GRADE GLIOMA SP-0532 Molecular biomarkers in glioma: Prognostic or predictive? W. Wick1 1 University Hospital Heidelberg, Deaprtment of Neurooncology, Heidelberg, Germany Promoter methylation of the O6-methyl-guaninemethyl transferase gene is considered relevant for treatment with alkylating chemotherapies for almost 15 years. Ten years ago the EORTC26981/22981 NCIC CE.3 trial demonstrated a predictive role for MGMT promoter methylation in patients with gliobastoma treated with temozolomide. Two phase trials in elderly patients confirmed that predictive role for the MGMT status resulting in a modification of clinical practice. In anaplastic gliomas, both the codeletion of 1p/19q as well as the MGMT promoter methylation are predictive for combined radiochemotherapy or alkylating (radio-) chemotherapy, respectively. The role of MGMT isdependent on mutation status of isocitratede hydrogenase, as mutated IDH confers a glioma CpG island methylator phenotype, both being prognostic and making also MGMT a prognostic biomarker. In the wild-type IDHsetting, MGMT is predictive. Other relevant prognostic parameters are loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene. More recently, also expression of n-myc downstream regulated gene 1 (NDRG1) has been associated with resistance to alkylating chemotherapy and CD95 ligand expression with response to anti-CD9 5ligand-directed therapy. SP-0533 Maximising benefit and minimising risk in the treatment of elderly patients with glioblastoma N. Laperriere1 1 Princess Margaret Cancer Centre, Radiation Oncology, Toronto, Canada The standard of care for patients with glioblastoma age 70 or less with a WHO performance status of 2 or better has been established as 6 weeks of radiotherapy with daily concurrent temozolomide and 6 months of adjuvant temozolomide. Subsequent analysis of this trial revealed a declining benefit of the addition of temozolomide to radiotherapy with increasing age, such that the benefit for patients older than 60 did not reach statistical significance. Population based data show a diminishing benefit from any treatment with older age, such that one must exercise caution in administering potentially toxic therapy to older patients with glioblastoma. A French randomized trial of post-operative radiotherapy versus supportive care to patients with glioblastoma age 70 or older demonstrated an improved median survival of 29 versus 17 weeks in 85 patients with a KPS of 70 or better. A Canadian randomized trial of 40 Gy in 15 fractions versus 60 Gy in 30 fractions in 100 patients age 60 or older revealed a median survival of 5.6 months for the 40 Gy arm versus 5.1 months for the 60Gy arm, no statistical difference. The Nordic randomized trial in patients age 60 and older incorporated 2 radiotherapy arms of 34 Gy in 10 fractions versus 60 Gy in 30 fractions, and there was no statistically significant difference in survival found between these 2 arms, but in patients age older than 70, there was a statistically significant reduction in survival for the 60 Gy arm versus the 34 Gy arm, suggesting possible toxicity of the higher dose arm as the possible reason for this difference. The NOA-08 German randomized trial of radiotherapy (54-60 Gy in 30) versus temozolomide (days 1-7, days 1521) found no statistical difference in survival, but did find that MGMT promoter methylated patients had better survival with temozolomide as opposed to radiotherapy, and vice versa for patients with unmethylated tumours, suggesting a possible strategy of temozolomide only for methylated patients and radiotherapy only for unmethylated patients. The NCIC CTG-EORTC randomized trial of 40 Gy in 15 fractions with and without concurrent and adjuvant temozolomide has recently completed accrual of 562 patients, and will provide data on the possible benefit of short course radiotherapy with temozolomide as an option for elderly patients with glioblastoma.
SP-0534 Do patients with glioblastoma benefit from IMRT?