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15: Oxygen ions achieve better tumour control probability in hypoxic tumours than carbon ions do
ICTR-PHE – 2014
S7
5
Institute Claudius Regaud, France IPNL
6
Hadrontherapy is an advanced form of radiotherapy able to cure very radioresistant tumors. It is developing since two decades mainly in Japan and Europe in Germany, Italy and Austria. The input of CERN has been important in its development in Europe. France is involved in that domain since 20 years thanks to its two protontherapy centers, ICPO in Orsay and Médicyc in Nice. This experience as well as the exploratory development of carbon ion therapy in the U.S.A., and the further clinical use in Japan and Europe, have given rise to projects in France for both a treatment center (ETOILE in Lyon) and a research center (ARCHADE in Caen). Different applied research programs have been associated to these projects involving many different teams located in different towns in France. To boost this domain of R&D a long term grant has been solicited to the French government in the frame of the National Program of Investments for the Future. To obtain this grant a great effort of coordination and gathering of all the involved teams, laboratories and projects had to be done. The result has been the “national infrastructure” France HADRON (FrHA) one unique organization constituting a distributed multicenter infrastructure. FrHA has been nominated and financed in 2012, up to 15M€, to spend from 2013 to 2019. FrHA includes 5 centers able to provide now or in the future hardware and beam time. These are Lyon (ETOILE), Caen (ARCHADE), Orsay (ICPO), Nice (Medicyc and IMPACT) and Toulouse (PERICLES). More than 20 scientific teams are federated in FrHA to develop a 4 WP’s scientific program encompassing all the former individual programs (see figure). This entity will be able to lead and promote this area of research and medical application by: coordinating and driving the national research and training program in hadrontherapy which ranges from particle fragmentation to clinical research, through dosimetry, radiobiology, imaging, control of target positioning, radiation protection and quality control instrumentation; organizing, facilitating and financing researchers' access to the particle beams required for the development of experimental work; financing part of the equipment of the research platforms. And ensuring the participation in international programs such as those already existing and actively invested by the French teams: ENLIGHT, Partner, ULICE, ENVISION, ENTERVISION. FrHA had its T0 the 1st March 2013 for financial items and on the 14th October 2013 for its activities. The Pr J.Balosso and JF.Habrand are the coordinators of FrHA. In the frame of FrHA, projects as ETOILE and ARCHADE are devoted to ensure an output to all these research efforts. The first one relies on a governmental decision (not yet obtained) as the national center for carbon ions radiotherapy for the French patients, and the second one, on local decisions as a R&D project based on the development of a new heavy ions cyclotron specie, the C400 of IBA.
Keywords: Carbontherapy, Applied research, National infrastructure 15 Oxygen ions achieve better tumour control probability in hypoxic tumours than carbon ions do N. Bassler1, O. Jäkel2, M. Krämer3, A. Lühr4,5, J. Overgaard6, L. Saksø Mortensen6, E. Scifoni3, B. Singers Sørensen6, J. Toftegaard1 1 Department of Physics and Astronomy, Aarhus University, Denmark 2 Heidelberg Ion Therapy, Universitätsklinikum Heidelberg, Germany 3 Biophysics Department, GSI Helmoltzzentrum für Schwerionenforschung, Darmstadt, Germany 4 National Center for Radiation Research in Oncology, OncoRay University Hospital, Dresden, Germany 5 Medical Faculty C.G. Carus Technische Universität Dresden, Dresden, Germany 6 Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark Purpose: In vitro experiments have demonstrated a wellestablished relationship between the oxygen enhancement ratio (OER) and linear energy transfer (LET), where OER approaches unity for high-LET values. However, high-LET radiation is also associated with an elevated risk for late effects in normal tissue. LET-painting restricts high-LET radiation to compartments that are found to be hypoxic, while applying lower LET radiation to normoxic tissues, thereby minimizing the risk for late effects. Methods: Carbon-12 and oxygen-16 ion treatment plans with four fields and with homogeneous dose in the target volume, are applied on an oropharyngeal cancer case with an identified hypoxic entity within the planning target volume (PTV). First we assume a fully normoxic tissue and optimize the target dose to a tumour control probability (TCP) of 95%. The primary particle energy fluence needed for this plan is pinned, and TCP is recalculated for three cases assuming hypoxia: 1) using the previously obtained conventional plan with homogenous fields 2) LET-painting while varying the hypoxic tumour volume in order to investigate the threshold volume where TCP can be established 3) LET-painting while adding a slight dose boost (5-20%) in the hypoxic subvolume to assess its impact on TCP. Results: The homogenous plan (1) yielded 0% TCP as expected. LET-painting with carbon-12 ions (2) can only achieve tumour control for hypoxic subvolumes smaller than 0.5 cm3. Using oxygen-16 ions, ~50 % TCP can be achieved for tumours with hypoxic subvolumes of up to 1 or 2 cm3.
S8 Tumour control can be achieved for tumours with even larger hypoxic subvolumes, if a slight dose boost is allowed in combination with LET-painting (3). Conclusion: A substantial TCP increase can be achieved when applying the LET-painting concept using oxygen-16 ions on hypoxic tumours, ideally with a slight dose boost.
Figure 1. TCP can be achieved in LET-painted plans such as this one. Within the CTV (green line) a hypoxic target is identified (black line). Using partially ramped fields, the LET is redistributed so the hypoxic volume is covered by high-LET radiation, lowering the OER herein. Keywords: LET-painting, heavy ion therapy 16 Measurement of charged particle yields emitted during irradiation with therapeutic proton and Carbon beams in view of the design of a new tool for the monitoring of hadrontherapy treatments G. Battistoni1, V. Patera1,2,3, I. Mattei1,2, M. Marafini3, A. Sarti1,2, A. Sciubba1,2, R. Faccini1,2, L. Piersanti1,2, C. La Tessa4, M. Van Stalle4, C. Schuy4 1 INFN Milano, Italy 2 Univ. Roma 1, Italy 3 Centro Fermi, Italy 4 GSI Purpose: The interaction of the radiation with the patient body in ion therapy yields to the production of secondary charged and neutral particles, whose detection can be used to monitor hadron therapy treatments. Experimental tests have been performed, and others are planned, to verify expectations and to guide the design of specific detectors. We have focused our interest on the detection of charged particles [1,2,3]. Experimental tests have been performed with Carbon and proton beam on a simple homogeneous tissue-like target (PMMA), at GSI and CNAO respectively. The emission region of particles has been detected with a drift chamber while a LYSO scintillator provided the time-offlight and residual energy, from which the kinetic energy spectra have been obtained. The measurements were performed with the setup at different angle with respect to the primary beam direction. Results have been analyzed and compared to Monte Carlo expectations based on the FLUKA Monte Carlo code [4]. The accuracy on the reconstruction of the emission profile of the fragments has been measured and its relationship with the position of the primary Bragg peak has been investigated. Based on the results, a method to monitor the dose profile and the position of the Bragg peak inside the target is proposed
ICTR-PHE – 2014 Materials/Methods: A scheme of the experimental setup is shown in Fig. 1. The beam rate has been monitored using plastic scintillator counters. Charged tracks have been identified and measured by means of A 21 cm long Drift Chamber (DC). Given the DC geometry, a particle traveling from the target to the LYSO detector will cross most of its twelve tracking planes. It has been operated with 1.8 kV sense wire voltage, Ar/CO2 (80/20) gas mixture and 30 mV discriminating threshold for the signals, achieving ~200 µm single cell spatial resolution and ~96% single cell efficiency. A scintillation detector, composed of an array of 4 LYSO crystals, 1.5x1.5x12 cm3 each, was placed downstream the drift chamber. The scintillation light of the crystals was detected with an EMI 9814B PMT. The energy and time calibration of the LYSO crystals have been previously studied and reported in literature.
Figure 1. To select events with charged particles arriving on the LYSO scintillator we exploited the information collected by the Drift Chamber. Given the DC geometry, an ion traveling from the target to the LYSO detector will cross most of its twelve tracking planes. The time of flight (TOF) between a signal recorded by the Start Counters and the LYSO array was measured with a Time-to-Digital Converter (TDC). The combination with energy deposition in LYSO and TOF allowed identification of particles. Results: Fluxes and velocity spectra of emitted particles have been obtained. The spatial distribution of the fragments has been characterized to investigate a possible correlation between its shape and the dose profile inside the target. These distributions can be also used to validate Monte Carlo predictions Conclusions: An important outcome of the emission shape study is that the experimental single track resolution needed to exploit the charged monitoring can be safely of the order of few millimeters without spoiling the precision achievable on longitudinal shape. The results obtained should be considered as preliminary to asses a practical application of this technique to the clinical practice. A first design of a profile detector is presented. Keywords: hadrontherapy, monitoring, detector References: [1] Agodi C. et al., “Charged particle’s flux measurements from PMMA irradiated by 80 MeV/u carbon ion beam”, JINST 7 (2012) P03001; [2] Henriquet P. et al., “Interaction vertex imaging (IVI) for carbon ion therapy monitoring: a feasibility study”. Physics in Med. And Biol. 54 (2012) 4655; [3] Gwosch K. et al., “Non invasive monitoring of therapeutic carbon ion beams in a homogeneous phantom by tracking of secondary ions”, Physics in Med. And Biol. 58 (2013) 3755; [4] A. Ferrari, P. R. Sala, A. Fasso , and J. Ranft, “FLUKA: a Multi-Particle Transport Code,” CERN, INFN, SLAC, CERN2005-10, INFN/TC_05/11, SLAC-R-773, 2005.
S7
5
Institute Claudius Regaud, France IPNL
6
Hadrontherapy is an advanced form of radiotherapy able to cure very radioresistant tumors. It is developing since two decades mainly in Japan and Europe in Germany, Italy and Austria. The input of CERN has been important in its development in Europe. France is involved in that domain since 20 years thanks to its two protontherapy centers, ICPO in Orsay and Médicyc in Nice. This experience as well as the exploratory development of carbon ion therapy in the U.S.A., and the further clinical use in Japan and Europe, have given rise to projects in France for both a treatment center (ETOILE in Lyon) and a research center (ARCHADE in Caen). Different applied research programs have been associated to these projects involving many different teams located in different towns in France. To boost this domain of R&D a long term grant has been solicited to the French government in the frame of the National Program of Investments for the Future. To obtain this grant a great effort of coordination and gathering of all the involved teams, laboratories and projects had to be done. The result has been the “national infrastructure” France HADRON (FrHA) one unique organization constituting a distributed multicenter infrastructure. FrHA has been nominated and financed in 2012, up to 15M€, to spend from 2013 to 2019. FrHA includes 5 centers able to provide now or in the future hardware and beam time. These are Lyon (ETOILE), Caen (ARCHADE), Orsay (ICPO), Nice (Medicyc and IMPACT) and Toulouse (PERICLES). More than 20 scientific teams are federated in FrHA to develop a 4 WP’s scientific program encompassing all the former individual programs (see figure). This entity will be able to lead and promote this area of research and medical application by: coordinating and driving the national research and training program in hadrontherapy which ranges from particle fragmentation to clinical research, through dosimetry, radiobiology, imaging, control of target positioning, radiation protection and quality control instrumentation; organizing, facilitating and financing researchers' access to the particle beams required for the development of experimental work; financing part of the equipment of the research platforms. And ensuring the participation in international programs such as those already existing and actively invested by the French teams: ENLIGHT, Partner, ULICE, ENVISION, ENTERVISION. FrHA had its T0 the 1st March 2013 for financial items and on the 14th October 2013 for its activities. The Pr J.Balosso and JF.Habrand are the coordinators of FrHA. In the frame of FrHA, projects as ETOILE and ARCHADE are devoted to ensure an output to all these research efforts. The first one relies on a governmental decision (not yet obtained) as the national center for carbon ions radiotherapy for the French patients, and the second one, on local decisions as a R&D project based on the development of a new heavy ions cyclotron specie, the C400 of IBA.
Keywords: Carbontherapy, Applied research, National infrastructure 15 Oxygen ions achieve better tumour control probability in hypoxic tumours than carbon ions do N. Bassler1, O. Jäkel2, M. Krämer3, A. Lühr4,5, J. Overgaard6, L. Saksø Mortensen6, E. Scifoni3, B. Singers Sørensen6, J. Toftegaard1 1 Department of Physics and Astronomy, Aarhus University, Denmark 2 Heidelberg Ion Therapy, Universitätsklinikum Heidelberg, Germany 3 Biophysics Department, GSI Helmoltzzentrum für Schwerionenforschung, Darmstadt, Germany 4 National Center for Radiation Research in Oncology, OncoRay University Hospital, Dresden, Germany 5 Medical Faculty C.G. Carus Technische Universität Dresden, Dresden, Germany 6 Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark Purpose: In vitro experiments have demonstrated a wellestablished relationship between the oxygen enhancement ratio (OER) and linear energy transfer (LET), where OER approaches unity for high-LET values. However, high-LET radiation is also associated with an elevated risk for late effects in normal tissue. LET-painting restricts high-LET radiation to compartments that are found to be hypoxic, while applying lower LET radiation to normoxic tissues, thereby minimizing the risk for late effects. Methods: Carbon-12 and oxygen-16 ion treatment plans with four fields and with homogeneous dose in the target volume, are applied on an oropharyngeal cancer case with an identified hypoxic entity within the planning target volume (PTV). First we assume a fully normoxic tissue and optimize the target dose to a tumour control probability (TCP) of 95%. The primary particle energy fluence needed for this plan is pinned, and TCP is recalculated for three cases assuming hypoxia: 1) using the previously obtained conventional plan with homogenous fields 2) LET-painting while varying the hypoxic tumour volume in order to investigate the threshold volume where TCP can be established 3) LET-painting while adding a slight dose boost (5-20%) in the hypoxic subvolume to assess its impact on TCP. Results: The homogenous plan (1) yielded 0% TCP as expected. LET-painting with carbon-12 ions (2) can only achieve tumour control for hypoxic subvolumes smaller than 0.5 cm3. Using oxygen-16 ions, ~50 % TCP can be achieved for tumours with hypoxic subvolumes of up to 1 or 2 cm3.
S8 Tumour control can be achieved for tumours with even larger hypoxic subvolumes, if a slight dose boost is allowed in combination with LET-painting (3). Conclusion: A substantial TCP increase can be achieved when applying the LET-painting concept using oxygen-16 ions on hypoxic tumours, ideally with a slight dose boost.
Figure 1. TCP can be achieved in LET-painted plans such as this one. Within the CTV (green line) a hypoxic target is identified (black line). Using partially ramped fields, the LET is redistributed so the hypoxic volume is covered by high-LET radiation, lowering the OER herein. Keywords: LET-painting, heavy ion therapy 16 Measurement of charged particle yields emitted during irradiation with therapeutic proton and Carbon beams in view of the design of a new tool for the monitoring of hadrontherapy treatments G. Battistoni1, V. Patera1,2,3, I. Mattei1,2, M. Marafini3, A. Sarti1,2, A. Sciubba1,2, R. Faccini1,2, L. Piersanti1,2, C. La Tessa4, M. Van Stalle4, C. Schuy4 1 INFN Milano, Italy 2 Univ. Roma 1, Italy 3 Centro Fermi, Italy 4 GSI Purpose: The interaction of the radiation with the patient body in ion therapy yields to the production of secondary charged and neutral particles, whose detection can be used to monitor hadron therapy treatments. Experimental tests have been performed, and others are planned, to verify expectations and to guide the design of specific detectors. We have focused our interest on the detection of charged particles [1,2,3]. Experimental tests have been performed with Carbon and proton beam on a simple homogeneous tissue-like target (PMMA), at GSI and CNAO respectively. The emission region of particles has been detected with a drift chamber while a LYSO scintillator provided the time-offlight and residual energy, from which the kinetic energy spectra have been obtained. The measurements were performed with the setup at different angle with respect to the primary beam direction. Results have been analyzed and compared to Monte Carlo expectations based on the FLUKA Monte Carlo code [4]. The accuracy on the reconstruction of the emission profile of the fragments has been measured and its relationship with the position of the primary Bragg peak has been investigated. Based on the results, a method to monitor the dose profile and the position of the Bragg peak inside the target is proposed
ICTR-PHE – 2014 Materials/Methods: A scheme of the experimental setup is shown in Fig. 1. The beam rate has been monitored using plastic scintillator counters. Charged tracks have been identified and measured by means of A 21 cm long Drift Chamber (DC). Given the DC geometry, a particle traveling from the target to the LYSO detector will cross most of its twelve tracking planes. It has been operated with 1.8 kV sense wire voltage, Ar/CO2 (80/20) gas mixture and 30 mV discriminating threshold for the signals, achieving ~200 µm single cell spatial resolution and ~96% single cell efficiency. A scintillation detector, composed of an array of 4 LYSO crystals, 1.5x1.5x12 cm3 each, was placed downstream the drift chamber. The scintillation light of the crystals was detected with an EMI 9814B PMT. The energy and time calibration of the LYSO crystals have been previously studied and reported in literature.
Figure 1. To select events with charged particles arriving on the LYSO scintillator we exploited the information collected by the Drift Chamber. Given the DC geometry, an ion traveling from the target to the LYSO detector will cross most of its twelve tracking planes. The time of flight (TOF) between a signal recorded by the Start Counters and the LYSO array was measured with a Time-to-Digital Converter (TDC). The combination with energy deposition in LYSO and TOF allowed identification of particles. Results: Fluxes and velocity spectra of emitted particles have been obtained. The spatial distribution of the fragments has been characterized to investigate a possible correlation between its shape and the dose profile inside the target. These distributions can be also used to validate Monte Carlo predictions Conclusions: An important outcome of the emission shape study is that the experimental single track resolution needed to exploit the charged monitoring can be safely of the order of few millimeters without spoiling the precision achievable on longitudinal shape. The results obtained should be considered as preliminary to asses a practical application of this technique to the clinical practice. A first design of a profile detector is presented. Keywords: hadrontherapy, monitoring, detector References: [1] Agodi C. et al., “Charged particle’s flux measurements from PMMA irradiated by 80 MeV/u carbon ion beam”, JINST 7 (2012) P03001; [2] Henriquet P. et al., “Interaction vertex imaging (IVI) for carbon ion therapy monitoring: a feasibility study”. Physics in Med. And Biol. 54 (2012) 4655; [3] Gwosch K. et al., “Non invasive monitoring of therapeutic carbon ion beams in a homogeneous phantom by tracking of secondary ions”, Physics in Med. And Biol. 58 (2013) 3755; [4] A. Ferrari, P. R. Sala, A. Fasso , and J. Ranft, “FLUKA: a Multi-Particle Transport Code,” CERN, INFN, SLAC, CERN2005-10, INFN/TC_05/11, SLAC-R-773, 2005.