- Email: [email protected]
SP-0579 COMBINATION OF TARGETED DRUGS WITH RADIOATHERAPY IN GLIOBASTOMA = FROM MECHANISMS TO THERAPY
S232
ESTRO 31
treatment techniques have not yet been determined and are unlikely to become apparent for many years, due to the long latency time for solid tumor induction. Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors who were exposed to γ-rays and neutrons. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. With increasing cure rates, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this review, emphasis was placed on doses relevant for radiotherapy with respect to radiation induced solid cancer. Simple radiation protection models should be used only with extreme care for risk estimates in radiotherapy, since they are developed exclusively for low dose. When applied to scatter radiation, such models can predict only a fraction of observed second malignancies. Better semi-empirical models include the effect of dose fractionation and represent the dose-response relationships more accurately. The involved uncertainties are still huge for most of the organs and tissues. A major reason for this is that the underlying processes of the induction of carcinoma and sarcoma are not well known. Most uncertainties are related to the time patterns of cancer induction, the population specific dependencies and to the organ specific cancer induction rates. For radiotherapy treatment plan optimization these factors are irrelevant, as a treatment plan comparison is performed for a patient of specific age, sex, etc. If a treatment plan is compared relative to another one only the shape of the dose-response curve (the so called risk-equivalent dose) is of importance and errors can be minimized. SP-0577 WHAT IS A STEM CELL AND WHY SHOULD I CARE M. Vooijs1 1 MAASTRO GROW Research Institute, Radiotherapy, Maastricht, The Netherlands I will discuss several aspects of stem cell biology and how these may impact on Radiation Oncology. These include “What is a stem cell? Where are stem cells located? What is a cancer stem cell? How relevant are stem cells for radiation treatment in normal tissues and in tumours? Recommended reading; Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer. 2008 May 30;8(7):545–554.
SYMPOSIUM: CURRENT PRACTICE AND CONTROVERSIES: BRAIN TUMOURS SP-0579 COMBINATION OF TARGETED DRUGS WITH RADIOATHERAPY GLIOBASTOMA = FROM MECHANISMS TO THERAPY E. Moyal-Cohen-Jonathan1 1 Institut Claudius Regaud, Department of Radiation Oncology and INSERM 1037 CRCT, Toulouse, France
IN
Despite significant progress obtained in the treatment of glioblastoma (GBM), the prognosis of these radioresistant, invasive and hypoxic tumors remains poor. The constant relapse after treatment of this tumour is in part due to its intra-cellular but also microenvironmental radioresistance largely controlled by growth factors and their receptors. Several pre-clinical studies have shown the involvement of EGFR but also angiogenic factors as VEGF, FGF-2, but also avb3 and avb5 integrins and their pathway in the control of glioblastoma tumor radiosensitivity but also in those of endothelial cells which in turn also control the tumor radiosensitivity. Moreover, some of these factors have been shown to control hypoxia in GBM also leading to radioresistance. Finally increasing studies show the involvement of GBM stem cells in aggressiveness and radioresistance as well as involvement of hypoxia in GBM reprogramming. Thus, inhibiting these different targets with targeting drugs leads to in vitro and in vivo GBM radiosensitization as well as decrease of hypoxia and vascularisation normalisation. Several clinical studies have been performed and are in progress associating these inhibitors to radiochemotherapy in first line treatment of patients with GBM. We will present the main biological pathways involved in GBM radioresistance as well as preclinical data associating inhibitors of this pathways to radiotherapy and then the main clinical trials currently developed based on these pre-clinical data. The importance of biomarkers in the
design of clinical trials and in the follow-up of the effects of these treatments will also be discussed SP-0580 LOW GRADE GLIOMAS / TREATMENT SEQUENCE (CURRENT PRACTICE AND FUTURE TRENDS) R.D. Kortmann1 1 Universität Leipzig, Radiation Therapy, Leipzig, Germany Background: The EORTC trial 22845 on the role of immediate postoperative radiotherapy in patients with supratentorial low-grade glioma revealed an advantage of immediate postoperative radiotherapy for progression free survival, but not for overall survival. It is still an open question in which clinical setting immediate radiotherapy should be considered and whether chemotherapy may become a useful alternative. Material and Methods: Reports in the literature spanning 60 years of radiation therapy were reviewed with respect to timing of radiotherapy, prognostic factors, dose prescriptions, modern treatment techniques and late effects. Data on chemotherapy were also reviewed. Based on these data the role of immediate postoperative radiotherapy or chemotherapy in adult low-grade glioma is presented. Results: Radiotherapy is able to control symptoms in up to 80% of cases. Malignant transformation occurs in 36 to 86 % of cases upon progressive disease. Long-term median survival crucially depends on prognostic factors and ranges between 12 months and 10 years. Radiotherapy will not cause neurocognitive dysfunctiions, provided that modern treatment techniques and moderate dose prescriptions are used. Recent series with small patient numbers indicate that chemotherapy using PCV or temozolomide may prolong median survival and induces response rates of 50%. Conclusions: The arguments for immediate postoperative irradiation include: low-grade gliomas respond to radiation, the tumours often display an aggressive pathobiological behaviour, patients with high risk profile may benefit from immediate radiotherapy in terms of progression-free and overall survival, modern focal radiotherapy is far less toxic than feared, radiation might be more effective at diagnosis than at progression. Modern technologies will contribute to a better functional outcome. Chemotherapy might be an alternative in immediate postoperative treatment. Its role, however, is unclear. The recently closed prospective trial of the EORTC addresses this issue in a randomised setting. SP-0581 TREATING BRAIN METASTASES: CURRENT APPROACHES CONTROVERSIES G. Minniti1 1 S. Andrea Hospital (Roma) and IRCCS Neuromed (IS) University Sapienza, Radiation Oncology, Rome and Pozzilli (IS), Italy
AND
Brain metastases have been reported in up to 40% in patients with cancer (). Most patients with brain metastases are treated with whole brain radiotherapy (WBRT) with a reported median survival of 3-6 months, and a significant proportion of patients who die of intracranial progressive disease a few months after treatment. The RTOG 9504 phase 3 trial reported on 333 patients with 1 to 3 brain metastases who received WBRT with or without radiosurgery (SRS) boost. It demonstrated a survival benefit for patients with a single brain metastasis, and improved control rate and KPS across all patients in the WBRT and SRS group. However, there was no survival difference in patients with multiple brain metastases and no difference in the rate of neurologic death. With the establishment of the efficacy of focal treatments, new controversies have arisen. One such controversy is whether WBRT is necessary after successful focal therapy (surgery or SRS). Two large randomized trials have compared SRS alone and SRS plus WBRT. In a series of 132 patients with 1-4 brain metastases randomly assigned to receive WBRT plus SRS or SRS alone no significant differences were reported in survival and 1-year local control. Although SRS alone was associated with increased intracranial progression as compared with WBRT plus SRS, no differences in the frequency of neurologic deaths and preservation of neurologic function were observed. Similarly, the recent EORTC 22952-26001 study on the adjuvant WBRT versus observation after SRS or surgical resection of 1-3 cerebral metastases showed that adjuvant WBRT was able to reduce the frequency of intracranial progression but failed to improve the median survival. These studies suggest that WBRT could
ESTRO 31
treatment techniques have not yet been determined and are unlikely to become apparent for many years, due to the long latency time for solid tumor induction. Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors who were exposed to γ-rays and neutrons. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. With increasing cure rates, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this review, emphasis was placed on doses relevant for radiotherapy with respect to radiation induced solid cancer. Simple radiation protection models should be used only with extreme care for risk estimates in radiotherapy, since they are developed exclusively for low dose. When applied to scatter radiation, such models can predict only a fraction of observed second malignancies. Better semi-empirical models include the effect of dose fractionation and represent the dose-response relationships more accurately. The involved uncertainties are still huge for most of the organs and tissues. A major reason for this is that the underlying processes of the induction of carcinoma and sarcoma are not well known. Most uncertainties are related to the time patterns of cancer induction, the population specific dependencies and to the organ specific cancer induction rates. For radiotherapy treatment plan optimization these factors are irrelevant, as a treatment plan comparison is performed for a patient of specific age, sex, etc. If a treatment plan is compared relative to another one only the shape of the dose-response curve (the so called risk-equivalent dose) is of importance and errors can be minimized. SP-0577 WHAT IS A STEM CELL AND WHY SHOULD I CARE M. Vooijs1 1 MAASTRO GROW Research Institute, Radiotherapy, Maastricht, The Netherlands I will discuss several aspects of stem cell biology and how these may impact on Radiation Oncology. These include “What is a stem cell? Where are stem cells located? What is a cancer stem cell? How relevant are stem cells for radiation treatment in normal tissues and in tumours? Recommended reading; Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer. 2008 May 30;8(7):545–554.
SYMPOSIUM: CURRENT PRACTICE AND CONTROVERSIES: BRAIN TUMOURS SP-0579 COMBINATION OF TARGETED DRUGS WITH RADIOATHERAPY GLIOBASTOMA = FROM MECHANISMS TO THERAPY E. Moyal-Cohen-Jonathan1 1 Institut Claudius Regaud, Department of Radiation Oncology and INSERM 1037 CRCT, Toulouse, France
IN
Despite significant progress obtained in the treatment of glioblastoma (GBM), the prognosis of these radioresistant, invasive and hypoxic tumors remains poor. The constant relapse after treatment of this tumour is in part due to its intra-cellular but also microenvironmental radioresistance largely controlled by growth factors and their receptors. Several pre-clinical studies have shown the involvement of EGFR but also angiogenic factors as VEGF, FGF-2, but also avb3 and avb5 integrins and their pathway in the control of glioblastoma tumor radiosensitivity but also in those of endothelial cells which in turn also control the tumor radiosensitivity. Moreover, some of these factors have been shown to control hypoxia in GBM also leading to radioresistance. Finally increasing studies show the involvement of GBM stem cells in aggressiveness and radioresistance as well as involvement of hypoxia in GBM reprogramming. Thus, inhibiting these different targets with targeting drugs leads to in vitro and in vivo GBM radiosensitization as well as decrease of hypoxia and vascularisation normalisation. Several clinical studies have been performed and are in progress associating these inhibitors to radiochemotherapy in first line treatment of patients with GBM. We will present the main biological pathways involved in GBM radioresistance as well as preclinical data associating inhibitors of this pathways to radiotherapy and then the main clinical trials currently developed based on these pre-clinical data. The importance of biomarkers in the
design of clinical trials and in the follow-up of the effects of these treatments will also be discussed SP-0580 LOW GRADE GLIOMAS / TREATMENT SEQUENCE (CURRENT PRACTICE AND FUTURE TRENDS) R.D. Kortmann1 1 Universität Leipzig, Radiation Therapy, Leipzig, Germany Background: The EORTC trial 22845 on the role of immediate postoperative radiotherapy in patients with supratentorial low-grade glioma revealed an advantage of immediate postoperative radiotherapy for progression free survival, but not for overall survival. It is still an open question in which clinical setting immediate radiotherapy should be considered and whether chemotherapy may become a useful alternative. Material and Methods: Reports in the literature spanning 60 years of radiation therapy were reviewed with respect to timing of radiotherapy, prognostic factors, dose prescriptions, modern treatment techniques and late effects. Data on chemotherapy were also reviewed. Based on these data the role of immediate postoperative radiotherapy or chemotherapy in adult low-grade glioma is presented. Results: Radiotherapy is able to control symptoms in up to 80% of cases. Malignant transformation occurs in 36 to 86 % of cases upon progressive disease. Long-term median survival crucially depends on prognostic factors and ranges between 12 months and 10 years. Radiotherapy will not cause neurocognitive dysfunctiions, provided that modern treatment techniques and moderate dose prescriptions are used. Recent series with small patient numbers indicate that chemotherapy using PCV or temozolomide may prolong median survival and induces response rates of 50%. Conclusions: The arguments for immediate postoperative irradiation include: low-grade gliomas respond to radiation, the tumours often display an aggressive pathobiological behaviour, patients with high risk profile may benefit from immediate radiotherapy in terms of progression-free and overall survival, modern focal radiotherapy is far less toxic than feared, radiation might be more effective at diagnosis than at progression. Modern technologies will contribute to a better functional outcome. Chemotherapy might be an alternative in immediate postoperative treatment. Its role, however, is unclear. The recently closed prospective trial of the EORTC addresses this issue in a randomised setting. SP-0581 TREATING BRAIN METASTASES: CURRENT APPROACHES CONTROVERSIES G. Minniti1 1 S. Andrea Hospital (Roma) and IRCCS Neuromed (IS) University Sapienza, Radiation Oncology, Rome and Pozzilli (IS), Italy
AND
Brain metastases have been reported in up to 40% in patients with cancer (). Most patients with brain metastases are treated with whole brain radiotherapy (WBRT) with a reported median survival of 3-6 months, and a significant proportion of patients who die of intracranial progressive disease a few months after treatment. The RTOG 9504 phase 3 trial reported on 333 patients with 1 to 3 brain metastases who received WBRT with or without radiosurgery (SRS) boost. It demonstrated a survival benefit for patients with a single brain metastasis, and improved control rate and KPS across all patients in the WBRT and SRS group. However, there was no survival difference in patients with multiple brain metastases and no difference in the rate of neurologic death. With the establishment of the efficacy of focal treatments, new controversies have arisen. One such controversy is whether WBRT is necessary after successful focal therapy (surgery or SRS). Two large randomized trials have compared SRS alone and SRS plus WBRT. In a series of 132 patients with 1-4 brain metastases randomly assigned to receive WBRT plus SRS or SRS alone no significant differences were reported in survival and 1-year local control. Although SRS alone was associated with increased intracranial progression as compared with WBRT plus SRS, no differences in the frequency of neurologic deaths and preservation of neurologic function were observed. Similarly, the recent EORTC 22952-26001 study on the adjuvant WBRT versus observation after SRS or surgical resection of 1-3 cerebral metastases showed that adjuvant WBRT was able to reduce the frequency of intracranial progression but failed to improve the median survival. These studies suggest that WBRT could