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187 Hypoxia-pet for radiation treatment planning in head and neck cancer
P r o f f e r e d Papers
March 12 - 15
tumor patients through plasma or tumor tissue, and correlation with clinical behaviour and response to (radio)therapy will provide information on involved signaling pathways and therewith uncover specific targets for brain tumor therapy. PEPTIDOMICS. Standardized blood collection and processing were found to be crucial steps to obtain optimal quality specimens for further proteomic analysis. Peptide capture using solid-phase extraction coupled to MALDI-TOF-MS allowed for high-resolution and reproducible serum peptide profiling. Mass spectrometry-based profiling results on the plasma samples from brain tumor patients versus healthy controls will be presented. C o n c l u s i o n s : Protein expression profiling allows for the detection of differentially expressed proteins in cancer and evaluation of the effects of (radio)therapy. Identification of the protein profiles from brain tumor patients through plasma or tumor tissue, and correlation with clinical behaviour and response to (radio)therapy will provide information on involved signaling pathways and therewith uncover specific targets for brain tumor therapy. 187 HYPOXIA-PET FOR RADIATION IN HEAD AND NECK CANCER
TREATMENT
PLANNING
A.L. Grosu*, M. Souvatzoglou, B. R6per*, M. Molls*, M. Schwaiger, H.J. Machulla, M. Piert Radiation Oncology*, Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, Section of Radiopharmacy, University TObingen, Germany The hypoxic fraction of solid tumors has been shown to predict animal and human tumor response to radiation The aim of this study was to integrate the hypoxia imaging with [18F]azomycin arabinoside positron emission tomography (18F-FAZA PET) in radiation treatment planning for patients with head and neck cancer. M a t e r i a l a n d m e t h o d s : FAZA-PET was performed in 10 patients with head and neck tumors (cT3-4, cN1-2,cM0), before radiochemotherapy. FAZAPET images were co-registered with the CT images and integrated in the radiation treatment planning system (BrainLAB). In 5 patients 18F-FAZA-PET and CT were performed independently, on two stand-alone machines and in 5 patients was used an integrated PET/CT system. The image fusion was based on external markers, on initial coordinates and on mutual information. The accuracy of the image fusion was evaluated using anatomical internal markers. The gross tumor volume for tumor (GTV-T) and lymph nodes (GTV-L) were outlined separately, based on CT/MRI/US information. Using the FAZAPET/CT co-registered images the Hypoxic Subvolume (HSV) was calculated for GTV-T and GTV-L, using the formula: min SUV (standard uptake value) in HSV > mean SUV (in contralateral neck muscle) x 1.5. Using IMRT, the GTV-T and GTV-L were encompassed in 90% isodose area, whereas the HSV was encompassed in 105% isodose area. Results: Import and co-registration of PET/CT data was automatically and userindependently possible by fusing the initial coordinates of both data sets for the hybrid PET/CT and mutual information for the two stand-alone systems. By comparing the integration of combined PET/CT data to the integration of stand-alone PET data both procedures were seen to be feasible for 18F FAZA tracers. However, the use of mask fixation during CT and PET is recommended for both methods. High 18F-FAZA uptake in tumor tissue (SUV tumor/SUV muscle > 1.5) was observed in 5/10 patients: in 3/10 patients the high tracer uptake was located only in the primary tumor, in 1/10 patients only in the lymph nodes and in 2/10 patients in both, tumor and lymph nodes. The mean GTV-T for all the 10 investigated patients was 58 cm 3, the mean GTV-L was 21 cm 3 and the mean HSV-Tumor and HSV-Lymph nodes were 7 cm 3 and 1 cm 3, respectively. For all the 10 patients mean SUV in tumor and lymph nodes was 2.2 (1.2-2.6), mean for the maximal tracer uptake in tumor and lymph nodes (5 patients) was 2.6 (1.5-3.4). HSV-Tumor represented 7-28% from the GTV-T and HSV-Lymph nodes represented 2-18% from the GTV-L. Using IMRT hypoxic and normoxic areas can be irradiated with different doses in the same session. C o n c l u s i o n s : This is the first study using 18FFAZA-PET for the visualization of hypoxia in vivo. 18F-FAZA-PET images can be integrated in the IMRT planning using standObjective:
$65
alone PET or integrated PET/CT. Further trials have to analyze the dynamic of this hypoxia marker under treatment and to establish its impact on radiation treatment planning in clinical studies. 188 RADIOBIOLOGICAL MODELLING OF T H E I N T E R P L A Y BETWEEN ACCELERATED REPOPULATION AND ALTERED FRACTIONATION SCHEDULES IN HEAD AND NECK CANCERS
L. Marcu, E. Bezak Royal Adelaide Hospital, Adelaide, Australia Overcoming accelerated repopulation during radiotherapy is one of the greatest challenges in the treatment of head and neck cancers. It has been shown before that the main mechanisms responsible for accelerated repopulation are: cell recruitment, accelerated stem cell division, and loss of asymmetry in stem cell division, the last being the major mechanism accountable for repopulation. Altered fractionation schedules have been designed and clinically tested in order to overcome accelerated repopulation. The most common schedules currently used are hyperfractionated radiotherapy and also accelerated radiotherapy. Several clinical trials (RTOG, TROG, CHART, DAHANCA) have tested the effectiveness of these protocols on head and neck tumours. The aim of the current work was to simulate some of the altered schedules used in clinical trials with the consideration of accelerated repopulation and to determine the optimal schedule-related parameters (dose/fraction, time interval between two consecutive fractions, and timing of treatment gap for accelerated radiotherapy) that should be used for the highest tumour control. Material and methods: The main repopulation mechanisms have been implemented into a computer-grown head and neck tumour using Monte Carlo techniques, and various altered fractionation schedules simulated. The parameters used were the following: 20% cell recruitment with each radiotherapy fraction, 8 h stem cell cycle time (reduction from the average 33 h cell cycle time considered for the head and neck cell population), and 12% loss in asymmetrical division of stem cells. Treatment with 1.1 Gy and also 1.2 Gy dose/fraction, twice a day, over 7 weeks of treatment, has been modelled, with intervals between fractions of 4 h, 6 h, and 8 h respectively. The accelerated fractionation scheme trialled by RTOG has been also simulated (1.6 Gy/fraction, twice a day, 6 hours apart, for 42 fractions with an interruption of two weeks for normal tissue recovery). A study on the timing of treatment break has been undertaken, with breaks employed after delivery of 20 fractions, 24 fractions, and 28 fractions of radiation dose, respectively. R e s u l t s : The focus of the study was on the influence of the schedule-related parameters on tumour control when accelerated repopulation during treatment is considered. The results show that the optimal dose/fraction to overcome accelerated repopulation in head and neck cancers with hyperfractionated radiotherapy is 1.2 Gy twice a day, with an interval between fractions of 6 hours. Furthermore, when planning treatment breaks during accelerated radiotherapy, the accurate timing is crucial in order to overcome clonogen repopulation, as the results show that even small variations in timing the break (4 fractions earlier or later) can lead to differences of up to 20% in tumour control. Conclusions: Both hyperfractionated and accelerated radiotherapy are superior to the conventional one in regards to tumour control, with hyperfractionation having slight advantage over acceleration. However, the accurate selection of schedulerelated parameters plays a crucial role in overcoming repopulation during radiotherapy. Future work will consider the effect of combined modality treatment (cisplatin-radiotherapy) in overcoming repopulation, which might differentiate further between the hyperfractionated and accelerated schemes. Objective:
189 T H E R E S P O N S E OF H E A D A N D N E C K T U M O U R S TO RADIOTHERAPY MAY BE INFLUENCED BY THE INTERACTION BETWEEN CELL P R O L I F E R A T I O N AND VASCULARIZATION
F.M. Buffa 1, S.M. Bentzen 2, B.M. Atasoya, F.M. Daley 1, P.I. Richman 4, S. Dische 4, G.D. Wilson s, M.I. Saunders 4,6
March 12 - 15
tumor patients through plasma or tumor tissue, and correlation with clinical behaviour and response to (radio)therapy will provide information on involved signaling pathways and therewith uncover specific targets for brain tumor therapy. PEPTIDOMICS. Standardized blood collection and processing were found to be crucial steps to obtain optimal quality specimens for further proteomic analysis. Peptide capture using solid-phase extraction coupled to MALDI-TOF-MS allowed for high-resolution and reproducible serum peptide profiling. Mass spectrometry-based profiling results on the plasma samples from brain tumor patients versus healthy controls will be presented. C o n c l u s i o n s : Protein expression profiling allows for the detection of differentially expressed proteins in cancer and evaluation of the effects of (radio)therapy. Identification of the protein profiles from brain tumor patients through plasma or tumor tissue, and correlation with clinical behaviour and response to (radio)therapy will provide information on involved signaling pathways and therewith uncover specific targets for brain tumor therapy. 187 HYPOXIA-PET FOR RADIATION IN HEAD AND NECK CANCER
TREATMENT
PLANNING
A.L. Grosu*, M. Souvatzoglou, B. R6per*, M. Molls*, M. Schwaiger, H.J. Machulla, M. Piert Radiation Oncology*, Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, Section of Radiopharmacy, University TObingen, Germany The hypoxic fraction of solid tumors has been shown to predict animal and human tumor response to radiation The aim of this study was to integrate the hypoxia imaging with [18F]azomycin arabinoside positron emission tomography (18F-FAZA PET) in radiation treatment planning for patients with head and neck cancer. M a t e r i a l a n d m e t h o d s : FAZA-PET was performed in 10 patients with head and neck tumors (cT3-4, cN1-2,cM0), before radiochemotherapy. FAZAPET images were co-registered with the CT images and integrated in the radiation treatment planning system (BrainLAB). In 5 patients 18F-FAZA-PET and CT were performed independently, on two stand-alone machines and in 5 patients was used an integrated PET/CT system. The image fusion was based on external markers, on initial coordinates and on mutual information. The accuracy of the image fusion was evaluated using anatomical internal markers. The gross tumor volume for tumor (GTV-T) and lymph nodes (GTV-L) were outlined separately, based on CT/MRI/US information. Using the FAZAPET/CT co-registered images the Hypoxic Subvolume (HSV) was calculated for GTV-T and GTV-L, using the formula: min SUV (standard uptake value) in HSV > mean SUV (in contralateral neck muscle) x 1.5. Using IMRT, the GTV-T and GTV-L were encompassed in 90% isodose area, whereas the HSV was encompassed in 105% isodose area. Results: Import and co-registration of PET/CT data was automatically and userindependently possible by fusing the initial coordinates of both data sets for the hybrid PET/CT and mutual information for the two stand-alone systems. By comparing the integration of combined PET/CT data to the integration of stand-alone PET data both procedures were seen to be feasible for 18F FAZA tracers. However, the use of mask fixation during CT and PET is recommended for both methods. High 18F-FAZA uptake in tumor tissue (SUV tumor/SUV muscle > 1.5) was observed in 5/10 patients: in 3/10 patients the high tracer uptake was located only in the primary tumor, in 1/10 patients only in the lymph nodes and in 2/10 patients in both, tumor and lymph nodes. The mean GTV-T for all the 10 investigated patients was 58 cm 3, the mean GTV-L was 21 cm 3 and the mean HSV-Tumor and HSV-Lymph nodes were 7 cm 3 and 1 cm 3, respectively. For all the 10 patients mean SUV in tumor and lymph nodes was 2.2 (1.2-2.6), mean for the maximal tracer uptake in tumor and lymph nodes (5 patients) was 2.6 (1.5-3.4). HSV-Tumor represented 7-28% from the GTV-T and HSV-Lymph nodes represented 2-18% from the GTV-L. Using IMRT hypoxic and normoxic areas can be irradiated with different doses in the same session. C o n c l u s i o n s : This is the first study using 18FFAZA-PET for the visualization of hypoxia in vivo. 18F-FAZA-PET images can be integrated in the IMRT planning using standObjective:
$65
alone PET or integrated PET/CT. Further trials have to analyze the dynamic of this hypoxia marker under treatment and to establish its impact on radiation treatment planning in clinical studies. 188 RADIOBIOLOGICAL MODELLING OF T H E I N T E R P L A Y BETWEEN ACCELERATED REPOPULATION AND ALTERED FRACTIONATION SCHEDULES IN HEAD AND NECK CANCERS
L. Marcu, E. Bezak Royal Adelaide Hospital, Adelaide, Australia Overcoming accelerated repopulation during radiotherapy is one of the greatest challenges in the treatment of head and neck cancers. It has been shown before that the main mechanisms responsible for accelerated repopulation are: cell recruitment, accelerated stem cell division, and loss of asymmetry in stem cell division, the last being the major mechanism accountable for repopulation. Altered fractionation schedules have been designed and clinically tested in order to overcome accelerated repopulation. The most common schedules currently used are hyperfractionated radiotherapy and also accelerated radiotherapy. Several clinical trials (RTOG, TROG, CHART, DAHANCA) have tested the effectiveness of these protocols on head and neck tumours. The aim of the current work was to simulate some of the altered schedules used in clinical trials with the consideration of accelerated repopulation and to determine the optimal schedule-related parameters (dose/fraction, time interval between two consecutive fractions, and timing of treatment gap for accelerated radiotherapy) that should be used for the highest tumour control. Material and methods: The main repopulation mechanisms have been implemented into a computer-grown head and neck tumour using Monte Carlo techniques, and various altered fractionation schedules simulated. The parameters used were the following: 20% cell recruitment with each radiotherapy fraction, 8 h stem cell cycle time (reduction from the average 33 h cell cycle time considered for the head and neck cell population), and 12% loss in asymmetrical division of stem cells. Treatment with 1.1 Gy and also 1.2 Gy dose/fraction, twice a day, over 7 weeks of treatment, has been modelled, with intervals between fractions of 4 h, 6 h, and 8 h respectively. The accelerated fractionation scheme trialled by RTOG has been also simulated (1.6 Gy/fraction, twice a day, 6 hours apart, for 42 fractions with an interruption of two weeks for normal tissue recovery). A study on the timing of treatment break has been undertaken, with breaks employed after delivery of 20 fractions, 24 fractions, and 28 fractions of radiation dose, respectively. R e s u l t s : The focus of the study was on the influence of the schedule-related parameters on tumour control when accelerated repopulation during treatment is considered. The results show that the optimal dose/fraction to overcome accelerated repopulation in head and neck cancers with hyperfractionated radiotherapy is 1.2 Gy twice a day, with an interval between fractions of 6 hours. Furthermore, when planning treatment breaks during accelerated radiotherapy, the accurate timing is crucial in order to overcome clonogen repopulation, as the results show that even small variations in timing the break (4 fractions earlier or later) can lead to differences of up to 20% in tumour control. Conclusions: Both hyperfractionated and accelerated radiotherapy are superior to the conventional one in regards to tumour control, with hyperfractionation having slight advantage over acceleration. However, the accurate selection of schedulerelated parameters plays a crucial role in overcoming repopulation during radiotherapy. Future work will consider the effect of combined modality treatment (cisplatin-radiotherapy) in overcoming repopulation, which might differentiate further between the hyperfractionated and accelerated schemes. Objective:
189 T H E R E S P O N S E OF H E A D A N D N E C K T U M O U R S TO RADIOTHERAPY MAY BE INFLUENCED BY THE INTERACTION BETWEEN CELL P R O L I F E R A T I O N AND VASCULARIZATION
F.M. Buffa 1, S.M. Bentzen 2, B.M. Atasoya, F.M. Daley 1, P.I. Richman 4, S. Dische 4, G.D. Wilson s, M.I. Saunders 4,6